U.S. patent number 4,220,795 [Application Number 05/933,663] was granted by the patent office on 1980-09-02 for cyclobutyl substituted derivatives of prostaglandin analogs.
This patent grant is currently assigned to Miles Laboratories, Inc.. Invention is credited to Henry C. Arndt, Harold C. Kluender.
United States Patent |
4,220,795 |
Kluender , et al. |
September 2, 1980 |
Cyclobutyl substituted derivatives of prostaglandin analogs
Abstract
Novel C15 cyclobutyl analogs or derivatives of prostaglandins of
the E-, A- and F-classes are useful modifiers of smooth muscle
activity. The compounds have valuable pharmacological properties
such as platelet antiaggregating agents, gastric antisecretory
agents and brochodilating agents.
Inventors: |
Kluender; Harold C. (Madison,
WI), Arndt; Henry C. (Madison, WI) |
Assignee: |
Miles Laboratories, Inc.
(Elkhart, IN)
|
Family
ID: |
25464324 |
Appl.
No.: |
05/933,663 |
Filed: |
August 14, 1978 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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808279 |
Jun 20, 1977 |
|
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|
|
693643 |
Jun 6, 1976 |
|
|
|
|
Current U.S.
Class: |
560/118; 549/430;
514/826; 556/485; 560/231; 562/505; 568/828; 568/833; 568/838;
514/822; 549/415; 549/453; 560/123; 562/500; 568/367; 568/834;
568/839 |
Current CPC
Class: |
C07C
45/59 (20130101); C07C 33/44 (20130101); C07C
45/68 (20130101); C07C 43/172 (20130101); C07C
45/63 (20130101); C07C 49/493 (20130101); C07C
45/52 (20130101); C07C 309/73 (20130101); C07C
29/147 (20130101); C07C 49/17 (20130101); C07C
45/455 (20130101); C07C 45/45 (20130101); C07C
29/48 (20130101); C07C 45/00 (20130101); C07C
29/03 (20130101); C07C 405/00 (20130101); C07C
29/03 (20130101); C07C 31/1336 (20130101); C07C
29/03 (20130101); C07C 33/44 (20130101); C07C
29/03 (20130101); C07C 33/025 (20130101); C07C
29/03 (20130101); C07C 31/20 (20130101); C07C
29/147 (20130101); C07C 33/44 (20130101); C07C
29/147 (20130101); C07C 31/1355 (20130101); C07C
29/147 (20130101); C07C 31/1336 (20130101); C07C
29/147 (20130101); C07C 33/025 (20130101); C07C
29/147 (20130101); C07C 31/20 (20130101); C07C
29/48 (20130101); C07C 33/44 (20130101); C07C
29/48 (20130101); C07C 33/025 (20130101); C07C
29/48 (20130101); C07C 31/1355 (20130101); C07C
29/48 (20130101); C07C 31/20 (20130101); C07C
29/48 (20130101); C07C 31/1336 (20130101); C07C
45/00 (20130101); C07C 49/567 (20130101); C07C
45/45 (20130101); C07C 49/293 (20130101); C07C
45/45 (20130101); C07C 49/203 (20130101); C07C
45/455 (20130101); C07C 49/493 (20130101); C07C
45/52 (20130101); C07C 49/493 (20130101); C07C
45/59 (20130101); C07C 49/17 (20130101); C07C
45/63 (20130101); C07C 49/567 (20130101); C07C
45/68 (20130101); C07C 49/573 (20130101); C07C
2601/04 (20170501); C07C 2601/08 (20170501) |
Current International
Class: |
C07C
29/147 (20060101); C07C 405/00 (20060101); C07C
29/00 (20060101); C07C 29/03 (20060101); C07C
29/48 (20060101); C07C 43/172 (20060101); C07C
43/00 (20060101); C07C 49/493 (20060101); C07C
45/00 (20060101); C07C 45/52 (20060101); C07C
45/68 (20060101); C07C 45/45 (20060101); C07C
45/63 (20060101); C07C 45/59 (20060101); C07C
309/73 (20060101); C07C 49/00 (20060101); C07C
33/00 (20060101); C07C 309/00 (20060101); C07C
33/44 (20060101); C07C 49/17 (20060101); C07L
179/00 () |
Field of
Search: |
;560/118 ;562/500 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gesstl; Robert
Attorney, Agent or Firm: Jeffers; Jerome L.
Parent Case Text
CROSS REFERENCED TO RELATED APPLICATION
This is a division of application Ser. No. 808,279, filed June 20,
1977 which in turn is a continuation-in-part application of Ser.
No. 693,643 filed on June 6, 1976, both abandoned.
Claims
What is claimed is:
1. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-16-methyl-9-oxoprost-13E-en-1-oate.
2. Methyl 11.alpha.,
15R-dihydroxy-16,18-methano-20,20-propano-9-oxoprost-13E-en-1-oate.
3. Methyl
11.alpha.,15S-dihydroxy-16,18-methano-20,20-propano-9-oxoprost-13E-en-1-oa
te.
4. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-19,20-ethano-9-oxoprost-13E-en-1-oat
e.
5. Methyl
11.alpha.,15S-dihydroxy-16,18-methano-19,20-ethano-9-oxoprost-13E-en-1-oat
e.
6. A compound having the formula: ##STR44##
Description
BACKGROUND OF THE INVENTION
Field of the Invention
Compounds of this invention are analogs of natural
prostaglandins.
Natural prostaglandins are twenty-carbon atom alicyclic compounds
related to prostanoic acid which has the following structure:
##STR1## By convention, the carbon atoms of I are numbered
sequentially from the carboxylic carbon atom. An important
stereochemical feature of I is the trans-orientation of the
sidechains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. All natural
prostaglandins have this orientation. In I, as elsewhere in this
specification, a dashed line ( ) indicates projection of a covalent
bond below the plane of a reference carbon atom
(alpha-configuration), while a wedged line ( ) represents direction
above that plane (beta-configuration). Those conventions apply to
all compounds subsequently discussed in this specification.
In one system of nomenclature suggested by N. A. Nelson (J. Med.
Chem., 17: 911 (1974), prostaglandins are named as derivatives or
modifications of the natural prostaglandins. In a second system,
the I.U.P.A.C. (International Union of Pure and Applied Chemistry)
system of nomenclature, prostaglandins are named as substituted
heptanoic acids. Yet a third system of nomenclature is frequently
used by those skilled in the prostaglandin art. In this third
system (also described by Nelson), all prostaglandins are named as
derivatives or modifications of prostanoic acid (structure I) or
prostane (the hydrocarbon equivalent of structure I). This system
is used by Chemical Abstracts and may become an I.U.P.A.C. accepted
system.
Natural prostaglandins have the structures, ##STR2## in which: L
and M may be ethylene or cis-vinylene radicals and the
five-membered ring ##STR3##
Prostaglandins are classified according to the functional groups
present in the fivemembered ring and the presence of double bonds
in the ring or chains. Prostaglandins of the A-class (PGA or
prostaglandin A) are characterized by an oxo group at C.sub.9 and a
double bond at C.sub.10 -C.sub.11 (.increment..sup.10, 11); those
of the B-class (PGB) have an oxo group at C.sub.9 and a double bond
at C.sub.8 -C.sub.12 (.increment..sup.8,12); compounds of the
C-class (PGC) contain an oxo group at C.sub.9 and a double bond at
C.sub.11 -C.sub.12 (.increment..sup.11,12); members of the D-class
(PGD) have an oxo group at C.sub.11 and an alpha-oriented hydroxy
group at C.sub.9 ; prostaglandins of the E-class (PGE) have an oxo
group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11 ;
and members of the F-class (PGF) have an alpha-directed hydroxyl
group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11.
Within each of the A-, B-, C-, D-, E-, and F-classes of
prostaglandins are three subclassifications based upon the presence
of double bonds in the side-chains at C.sub.5 -C.sub.6, C.sub.13
-C.sub.14, or C.sub.17 -C.sub.18. The presence of a
trans-unsaturated bond only at C.sub.13 -C.sub.14 is indicated by
the subscript numeral 1; thus, for example, PGE.sub.1 (or
prostaglandin E.sub.1) denotes a prostaglandin of the E-type (oxo
group at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a
trans-double bond at C.sub.13 -C.sub.14. The presence of both a
trans-double bond at C.sub.13 -C.sub.14 and a cis-double bond at
C.sub.5 -C.sub.6 is denoted by the subscript numeral 2; for
example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13
-C.sub.14, a cis-double bond at C.sub.5 -C.sub.6 and a cis-double
bond at C.sub.17 -C.sub.18 is indicated by the subscript numeral 3;
for example, PGE.sub.3. The above notations apply to prostaglandins
of the A-, B-, C-, D-, and F-series as well, however, in the latter
the alpha-orientation of the hydroxyl group at C.sub.9 is indicated
by the subscript Greek letter .alpha. after the numerical
subscript.
The three systems of nomenclature as they apply to natural
PGF.sub.3.alpha. are shown below: ##STR4## Nelson System:
Prostaglandin F.sub.3.alpha. or PGF.sub.3.alpha. (shortened
form)
I.U.P.A.C. System:
7-[3R,5S-Dihydroxy-2S-(3S-hydroxy-1E,5Z-octadienyl)-cyclopent-1R-yl]-5Z-hep
tenoic acid
Third System (Chemical Abstracts):
(5Z, 9.alpha., 11.alpha., 13E, 15S,
17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oic acid.
It is important to note that in all natural prostaglandins there is
an alpha-oriented hydroxyl group at C.sub.15. In the
Cahn-Ingold-Prelog system of defining stereochemistry, that
C.sub.15 hydroxyl group is in the S-configuration. The
Cahn-Ingold-Prelog system is used to define stereochemistry of any
asymmetric center outside of the carbocyclic ring in all three
systems of nomenclature described above. This is in contrast to
some prostaglandin literature in which the .alpha.,.beta.
designations are used, even at C.sub.15.
11-Deoxy derivatives of PGE and PGF molecules do not occur as such
in nature, but constitute a class of compounds which possess
biological activity related to the parent compounds. Formula II
represents 11-deoxy PGE and PGF compounds when: ##STR5## In this
formula, and others of this patent specification a swung dash or
serpentine line (.about.) denotes a covalent bond which can be
either in the alpha configuration (projecting below the plane of a
reference carbon atom) or in the beta configuration (projecting
above the plane of a reference carbon atom).
PGF.sub..beta. molecules also do not occur as such in nature, but
constitute a class of compounds which possess biological activity
related to the parent comounds. Formula II represents
PGF.sub..beta. compounds when: ##STR6##
9-Deoxy derivatives of PGE do not occur as such in nature, but
constitute a class of compounds which possess biological activity
related to the parent compounds. Formula II represents 9-deoxy PGE
compounds when: ##STR7##
9-Deoxy-.increment..sup.9,10 derivatives of PGE do not occur as
such in nature, but constitute a class of compounds which possess
biological activity related to the parent compounds. Formula II
represent 9deoxy-.increment..sup.9,10 PGE compounds when:
##STR8##
9a-Homo- and 9a-homo-11-deoxy-derivative of PGE and PGF molecules
do not occur as such in nature, but constitute a class of compounds
which possess biological activity related to the parent compounds.
Formula II represents 9a-homo- and 9a-homo-11-deoxy-compounds of
PGE and PGF when: ##STR9##
11a-Homo- derivatives of PGE, PGF and PGA molecules do not occur as
such in nature, but constitute classes of compounds which are
expected to posses biological activity related to the parent
compounds. Formula II represents 11a-homo- derivatives of PGE, PGF
and PGA molecules when: ##STR10##
11-Epi-PGE and PGF molecules do not occur as such in nature, but
constitute classes of compounds which possess biological activity
related to the parent compounds. Formula II represents
11-epi-compounds of PGE and PGF when: ##STR11##
8iso-, 12iso or 8,12-bis iso (ent) prostaglandins do not occur as
such in nature, but constitute classes of compounds which possess
biological activity related to the parent compounds. Formula II
represents 8iso-, 12iso- or 8,12-bis iso (ent) compounds when:
##STR12## These iso modifications of Formula II may be divided into
all of the sub-classes with varying ring oxygenation as described
above.
Recent research indicates that prostaglandins are ubiquitous in
animal tissues and that prostaglandins, as well as their synthetic
analogs, have important biochemical and physiological effects in
mammalian endocrine, reproductive, central and peripheral nervous,
sensory, gastrointestinal, hematic, respiratory, cardiovascular,
and renal systems.
In mammalian endocrine systems, experimental evidence indicates
prostaglandins are involved in the control of hormone synthesis or
release in hormone-secretory glands. In rats, for example,
PGE.sub.1 and PGE.sub.2 increase release of growth hormone while
PGA.sub.1 increased synthesis of that hormone. In sheep, PGE.sub.1
and PGF.sub.1.alpha. inhibit ovarian progesterone secretion. In a
variety of mammals, PGF.sub.1.alpha. and PGF.sub.2.alpha. act as
luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha.
and PGF.sub.1.beta. increase thyroid activity. In hypophysectomized
rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.alpha. stimulate
steroidogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the
smooth muscle of the vas deferens. In the female reproductive
system, PGE and PGF.sub..alpha. compounds contract uterine smooth
muscle. In general, PGE, PGB and PGA compounds relax in vitro human
uterine nuscle strips, whle those of the PGF.sub..alpha. class
contract such isolated preparations. PGE compounds in general
promote fertility in the female reproductive system while
PGF.sub.2.alpha. has contragestational effects. PGF.sub.2.alpha.
also appears to be involved in the mechanism of menstruation. In
general, PGF.sub.2 exerts potent oxytocic effects in inducing
labor, while PGF.sub.2.alpha. induces spontaneous abortions in
early pregnancy
PGF.sub..alpha. and PGE compounds have been isolated from a variety
of nervous tissue and they seem to act as neurotransmitters.
PGE.sub.1 retards whereas PGF.sub.2.alpha. facilitates transmission
in motor pathways in the central nervous system. It has been
reported that PGE.sub.1 and PGE.sub.2 inhibit transmitter release
from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth
muscle to vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1 and
PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar
activity in man.
In most mammalian respiratory tracts, compounds of the PGE and PGF
class relax in vitro preparations of tracheal smooth muscle. In
that preparation, PGE.sub.1 and PGE.sub.2 relax while
PGF.sub.2.alpha. contracts the smooth muscle. PGE and PGF compounds
are normally found in the human lung, and it is postulated that
some cases of bronchial asthma involve an imbalance in the
production or metabolism of those compounds.
Prostaglandins are involved in certain hematic mechanisms in
mammals, PGE.sub.1, for example, inhibits thrombogenesis in vitro
through its effects on blood platelets.
In a variety of mammalian cardiovascular systems, compounds of the
PGE and PGA class are vasodilators whereas those of the
PGF.sub..alpha. class vasoconstrictors, by virtue of their action
on vascular smooth muscle.
Prostaglandins are naturally found in the kidney and reverse
experimental and clinical renoprival hypertension.
The clinical implications of prostaglandins and their analogs are
far-ranging and include, but are not limited to the following: in
obstetrics and gynecology, they may be useful in fertility control,
treatment of menstrual disorders, induction of labor, and
correction of hormone disorders; in gastroenterology, they may be
useful in the treatment of peptic ulcers and various disorders
involving motility, secretion, and absorption in the
gastrointestinal tract; in the respiratory area, they may be
beneficial in therapy of bronchial asthma and other diseases
involving bronchoconstriction; in hematology, they may have utility
as anticlotting agents in diseases such as venous thrombosis,
thrombotic coronary occlusion and other diseases involving thrombi;
in circulatory diseases they have therapeutic utility in
hypertension, peripheral vasopathies, and cardiac disorders.
For a more complete review of chemical, physiological and
pharmacological aspects of the prostaglandin, consult the following
references: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York,
Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180: 1-568 (1971): and
Higgins and Braunwald, J. Am. Med. Assn., 53: 92-112 (1972).
DESCRIPTION OF THE PRIOR ART
South African Patent No. 7,308,595 discloses
15-substituted-.omega.-pentanorprostaglandins, wherein the
substituent is a cycloalkyl of from three to ten carbon atoms,
1-adamantyl, 2-norbornyl or 2-indanyl and possesses increased
tissue specificity of action over the parent prostaglandins.
Especially preferred are the
16-(1-adamantyl)-.omega.-tetranorprostaglandins and the
16-(cyclohexyl)-.upsilon.-tetranorprostaglandins of the PGE.sub.2
and the PGF.sub.2.alpha. classes.
U.S. Pat. No. 3,884,969 discloses selected
15-substituted-11-deoxy-PGE.sub.1 and PGE.sub.2 acids and esters,
wherein the substituent is a cycloalkyl having from 3 to 9 carbon
atoms, cycloalkenyl having from 5 to 9 carbon atoms, mono or
di-lower alkyl substituted cycloalkenyl groups having from 5 to 9
carbon atoms in the ring and adamantyl groups.
German Patent No. 2,510,818, laid open Sept. 18, 1975, discloses
15-cyclobutyl-prostaglandin acids and esters as having selective
gastric acid secretory and bronchodilatory effects.
U.S. Pat. No. 3,867,375 discloses various reagents for preparing
and method of preparing natural prostaglandins.
SUMMARY
Novel and useful 15-cyclobutyl analogs of prostaglandin primary
alcohols having the following structural Formula III are included
in the subject matter of this invention: ##STR13## In Formula III:
D is a R-hydroxymethylene, S-hydroxymethylene or acetoxymethylene
radical;
G is a methylene, .alpha.-hydroxymethylene, .beta.-hydroxymethylene
or methine radical such that G is methine only when J is
methine;
J is a methylene, ethylene or methine radical such that J is
ethylene only when G is methylene and J is methine only when G is
methine to form a carbon-carbon double covalent bond between G and
J;
L is carbonyl, .alpha.-hydroxymethylene or .beta.-hydroxymethylene
radical;
Q is ethylene or Z-vinylene radical;
p is an integer having a value of from 1 to 4, preferably a value
of 2 or 3;
T is a hydroxymethyl or acetoxymethylene radical;
M.sub.1 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms;
M.sub.2 is hydrogen or -(CH.sub.2).sub.n M.sub.4 where n is zero or
an integer having a value of from 1 to 5 and where M.sub.4 is
hydrogen or cycloalkyl having from 3 to 12 carbon atoms; and
M.sub.3 is hydrogen or lower alkyl having 1 to 3 carbon atoms.
The numbering system and stereochemistry nomenclature used for the
prostaglandins of this invention are according to the Chemical
Abstracts system which employs prostane or prostanoic acid as the
stereoparent compound. In Formula III, a dashed line ( ) indicates
projection of a covalent bond below the plane of a reference carbon
atom (alpha configuration); a wedged line ( ) represents direction
above that plane (beta configuration) and a swung dash or
serpentine line (.about.) denotes a covalent bond which can be
either the alpha or beta configuration. As used herein cis or trans
isomerism around double bonds respectively is designated by affixes
Z (zusammen) and E (entgegen). Chirality around asymmetric carbon
atoms in the carbocyclic ring is designated by affixes .alpha.
(alpha) and .beta. (beta). Chirality around asymmetric carbon atoms
in the alkyl side chains is designated by affixes R (rectus) and S
(sinister) according to the Cahn-Ingold-Prelog system of defining
stereochemistry.
Analogs or derivatives of the E-, A- and F-classes of the natural
prostaglandin primary alcohols are represented by Formula III.
Thus, when L is carbonyl, J is methylene or ethylene and G is
methylene or hydroxymethylene such that J is ethylene only when G
is methylene and T, p, Q, D, M.sub.1, M.sub.2 and M.sub.3 are as
defined above, III represents analogs of the E-class,
11-deoxy-E-class or 9.alpha.-homo-11-deoxy-E-class (E.sub.1 when Q
is ethylene and E.sub.2 when Q is Z-vinylene) of prostaglandins:
##STR14##
When L is carbonyl, J is methylene and G is
.alpha.-hydroxymethylene or .beta.-hydroxymethylene and T is as
defined above, III represents analogs of the E-class of
prostaglandins: ##STR15##
When L is carbonyl and both J and G are methylene and T is as
defined above, III represents analogs of the 11-deoxy-E-class of
prostaglandins: ##STR16##
When L is carbonyl, J is ethylene, G is methylene and T is as
defined above, III represents analogs of
9.alpha.-homo-II-deoxy-prostaglandin E.sub.2 : ##STR17##
When L is carbonyl and both J and G are methine radicals, III
represents analogs of the A-class (A.sub.1 when Q is ethylene and
A.sub.2 when Q is Z-vinylene) of prostaglandins: ##STR18##
When L is .alpha.-hydroxymethylene or .beta.-hydroxymethylene; J is
methylene or ethylene; G is .alpha.-hydroxymethylene,
.beta.-hydroxymethylene or methylene such that J is ethylene only
when G is methylene, III represents analogs of PGF.sub..alpha.,
PGF.sub..beta., 11-deoxy-PGF.sub..alpha., 11-deoxy-PGF.sub..beta.,
9a-homo-11-deoxy PGF.sub..alpha. and
9a-homo-11-deoxy-PGF.sub..beta. (F.sub.1 when Q is ethylene and
F.sub.2 when Q is Z-vinylene); ##STR19##
When L is .alpha.-hydroxymethylene or .beta.-hydroxymethylene; J is
methylene; and G is .alpha.-hydroxymethylene, III represents
analogs of PGF.sub..alpha. and PGF.sub..beta. : ##STR20##
Also included in the subject matter of this invention are the novel
and useful C-15-cyclobutyl analogs of prostaglandins acids and
esters of structural Formula III. ##STR21## In Formula III: D is a
R-hydroxymethylene, S-hydroxymethylene or acetoxymethylene
radical;
G is an .alpha.-hydroxymethylene, .beta.-hydroxymethylene or
methine radical such that G is methine only when J is methine;
J is a methylene or methine radical such that J is methine only
when G is methine to form a carbon-carbon double covalent bond
between G and J;
L is carbonyl, .alpha.-hydroxymethylene or .beta.-hydroxymethylene
radical;
Q is ethylene or Z-vinylene radical;
p is an integer having a value of 2 or 3;
T is an alkoxycarbonyl having from 1 to 3 carbon atoms inclusive in
the alkyl chain, carboxyl or pharmacologically acceptable nontoxic
carboxy salts thereof;
M.sub.1 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms;
M.sub.2 is hydrogen or -(CH.sub.2).sub.n M.sub.4 where n is 0 or an
integer having a value of from 1 to 5 and where M.sub.4 is hydrogen
or cycloalkyl having from 3 to 12 carbon atoms, provided that
M.sub.1 and M.sub.2 are not both hydrogen at the same time and
M.sub.4 is not hydrogen when n=0; and
M.sub.3 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms.
Analogs or derivatives of the E-, A- and F-classes of the natural
prostaglandin acids and esters are represented by the above Formula
III. Thus when L is carbonyl, J is methylene and G is
.alpha.-hydroxymethylene or .beta.-hydroxymethylene and T is an
alkoxycarbonyl, carboxyl or salts thereof, III represents analogs
of the E-class (E.sub.1 when Q is ethylene and E.sub.2 when Q is
Z-vinylene) of prostaglandin acids and esters: ##STR22##
When L is carbonyl and both J and G are methine radicals, III
represents analogs of the A-class (A.sub.1 when Q is ethylene and
A.sub.2 when Q is Z-vinylene) of prostaglandin acids and esters:
##STR23##
When L is .alpha.-hydroxymethylene or .beta.-hydroxymethylene; J is
methylene; and G is .alpha.-hydroxymethylene, III represents
analogs of PGF.sub..alpha. and PGF.sub..beta. (F.sub.1 when Q is
ethylene and F.sub.2 when Q is Z-vinylene): ##STR24##
Useful intermediates in the preparation of compounds of Formula III
are represented by the formula: ##STR25## In Formula IV; X is an
iodo or bromo radical;
A is an acid-labile hydroxyl-protecting group selected from the
class consisting of 1-ethoxyethyl; trimethylsilyl;
tert-butyl-dimethylsilyl; 2-ethoxy-prop-2-yl; tetrahydropyran-2-yl
or triphenylmethyl radicals;
M.sub.1 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms;
M.sub.2 is hydrogen, lower alkyl having from 1 to 3 carbon atoms,
or -(CH.sub.2).sub.n M.sub.4 where n is 0 or an integer having a
value of from 1 to 5 and where M.sub.4 is hydrogen or cycloalkyl
having from 3 to 12 carbon atoms, provided that M.sub.1 and M.sub.2
are not both hydrogen at the same time; and
M.sub.3 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms.
A useful process, included in this invention, for preparing
compounds of the formula ##STR26## is disclosed wherein: D is a
R-hydroxymethylene or S-hydroxymethylene or acetoxy-methylene
radical;
G is a methylene, .alpha.-hydroxymethylene, .beta.-hydroxymethylene
or methine radical such that G is methine only when J is
methine;
J is a methylene, ethylene or methine radical such that J is
ethylene only when G is methylene and J is methine only when G is
methine to form a carbon-carbon double bond between G and J;
L is a carbonyl, .alpha.-hydroxymethylene or
.beta.-hydroxymethylene radical;
Q is an ethylene or Z-vinylene radical;
p is an integer having a value of 1 to 4 inclusive;
T is a hydroxymethyl or acetoxymethylene radical;
M.sub.1 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms;
M.sub.2 is hydrogen or -(CH.sub.2).sub.n M.sub.4 where n is zero or
an integer having a value of from 1 to 5 and M.sub.4 is a
cycloalkyl having from 3 to 12 carbon atoms; and M.sub.3 is
hydrogen or lower alkyl having from 1 to 3 carbon atoms; which
comprises contacting a compound of the formula: ##STR27## wherein:
X is an iodo- or bromo-radical;
A is an acid-labile hydroxyl-protecting group selected from the
class consisting of 1-ethoxyethylene, trimethylsilyl,
tert-butyldimethylsilyl, 2-ethoxyprop-2-yl, tetrahydropyran-2-yl or
triphenylmethyl radicals; and the substituent M.sub.1, M.sub.2 and
M.sub.3 are as hereinabove defined, with a reagent selected from
the class consisting of metallic lithium, lower alkyl lithium,
magnesium or lower alkyl magnesium in an inert solvent under an
inert atmosphere; contacting the reaction mixture with a solvent
soluble copper(I) complex such as copper(I) pentyne,
tri-n-butylphosphine-copper(I) iodide, hexamethylphosphorus
triamide-copper(I) iodide or copper(I) thiophenolate; and
contacting the resultant reaction mixture with a compound of the
formula: ##STR28## wherein: G' is methylene, .alpha.- or
.beta.-hydroxymethylene radical protected with an
acid-labile-protecting group A;
J is a methylene or ethylene radical such that J is ethylene only
when G' is methylene; and
Q, p and A are as defined above;
in an inert solvent for a period of time sufficient for a
substantial degree of conjugate 1,4 addition to take place to form
an acid-labile hydroxyl-protected intermediate compound,
hydrolyzing the so-formed intermediate compound and recovering the
so-formed compounds having Formula III from the reaction
mixture.
Another useful process, included in this invention, for preparing
compounds of the formula: ##STR29## is disclosed wherein: D is a
R-hydroxymethylene, S-hydroxymethylene or acetoxymethylene
radical;
G is an .alpha.-hydroxymethylene, .beta.-hydroxymethylene or
methine radical such that G is methine only when J is methine;
J is a methylene or methine radical such that J is methine only
when G is methine to form a carbon-carbon double bond between G and
J;
L is a carbonyl, .alpha.-hydroxymethylene or
.beta.-hydroxymethylene radical;
Q is an ethylene or Z-vinylene radical;
T is an alkoxycarbonyl having from 1 to 3 carbon atoms inclusive in
the alkyl chain, carboxyl or pharmacologically acceptable nontoxic
carboxy salts thereof;
M.sub.1 is hydrogen or lower alkyl having from 1 to 5 carbon
atoms;
M.sub.2 is hydrogen or -(CH.sub.2).sub.n M.sub.4 where n is 0 or an
integer having a value of from 1 to 5 and where M.sub.4 is hydrogen
or cycloalkyl having from 3 to 12 carbon atoms, provided that
M.sub.1 and M.sub.2 are not both hydrogen at the same time; and
M.sub.3 is hydrogen or lower alkyl of 1 to 5 carbon atoms; which
comprises contacting a compound of the formula: ##STR30## wherein:
X is an iodo- or bromo-radical;
A is an acid-labile hydroxyl-protecting group selected from the
class consisting of 1-ethoxyethylene, trimethylsilyl,
tert-butyldimethylsilyl, 2-ethoxyprop-2-yl, tetrahydropyran-2-yl,
or triphenylmethyl radical; and
the substituents M.sub.1, M.sub.2 and M.sub.3 are as defined above,
with a reagent selected from the glass consisting of metallic
lithium, lower alkyl lithium metallic magnesium or lower alkyl
magnesium, in an inert solvent under an inert atmosphere;
contacting the reaction mixture with a solvent soluble copper(I)
complex such as copper(I) pentyne, tri-n-butylphosphine-copper(I)
iodide, hexamethylphosphorus triamidecopper(I) iodide or copper(I)
thiophendate; and contacting the resultant reaction mixture with a
compound of the formula: ##STR31## wherein: G' is methylene,
.alpha.- or .beta.-hydroxymethylene radical protected with an
acid-labile protecting group-A;
J is a methylene or ethylene radical such that J is ethylene only
when G' is methylene;
T is an alkoxycarbonyl having from 1 to 3 carbon atoms inclusive in
the alkyl chain; and
Q is as defined above; in an inert solvent for a period of time
sufficient for substantial degree of conjugate 1,4 addition to take
place to form an acid-labile hydroxyl-protected intermediate
compound, hydrolyzing the so-formed intermediate compound and
recovering the so-formed coumpounds having Formula III from the
reaction mixture.
DESCRIPTION OF THE INVENTION
Compounds having Formula III are prepared via the 1,4-conjugate
addition of organocopper reagents to cyclopentenones as reported by
Sih, et. al. (J. Amer. Chem. Soc., 97: 857, 865 [1975], and
references cited therein). The novel compounds of Formula III are
prepared according to the reaction sequence depicted in Table
A.
TABLE A
__________________________________________________________________________
##STR32## ##STR33## ##STR34## ##STR35##
__________________________________________________________________________
In Table A, Compound IV, where X is an iodo or bromo radical and A
is an acid-labile hydroxyl-protecting group, is contacted and
reacted with metallic lithium or a lower alkyl lithium (Compound V)
at from about -80.degree. to 0.degree. C. for about 0.25 to 3.0 hr
in an inert solvent, such as ether, tetrahydrofuran, hexane,
pentane, toluene, mixtures thereof and the like, under an inert
atmosphere, such as argon, nitrogen and the like. Copper(I) complex
(Compound VI) is added, usually as a solution in an inert solvent,
to the reaction mixture and the mixture is then stirred at less
than about -20.degree. C. for about 0.25 to 1.0 hr. A solution of
Compound VII, where G' is methylene or .dbd.CHOA and T' is
--CH.sub.2 OA or alkoxycarbonyl, usually in an inert solvent, is
added to the reaction mixture which is then allowed to warm to
about -20.degree. to 25.degree. C. over a 0.5 to 5 hr period to
yield the intermediate Compound VIII after quenching with a proton
donor. Treatment of the latter compound under hydrolysis conditions
such as with a weakly-acidic water mixture, such as acetic
acid-water (65:35 V/V) with 10% tetrahydrofuran, under an inert
atmosphere at a temperature of about 20.degree. to 45.degree. C.
for about 0.5 to 48 hr cleaves the acid-labile hydroxyl-protecting
groups (described in J. Amer. Chem. Soc.; 94:6194 [1972]) to yield
Compound IIIa.
Where G and J of Compound IIIa are respectively hydroxymethylene
and methylene, dehydration of Compound IIIa with a weakly-acidic
water mixture, such as acetic acid-water, at about 60.degree. to
80.degree. C. (described in J. Org. Chem.; 34:3553 [1969]) yields
Compound IIIe. Compound IIIe is also obtained as a byproduct of the
acidic hydrolysis of Compound VIII.
Reduction of Compound IIIa with sodium borohydride in an inert
alcoholic or other suitable polar solvent (described in J. Org.
Chem.; 34:3552 [1969]) yields Compound IIIf.
When T and G of Compound IIIa are respectively alkoxycarbonyl and
methylene, and when T of Compound IIIf is alkoxycarbonyl, cleavage
of the ester group with a base, such as sodium hydroxide or
potassium hydroxide in a mixed organic solvent such as
water-tetrahydrofuran, water-p-dioxane or water-alcohol (described
in J. Amer. Chem. Soc., 94:7823 [1973]) yields the corresponding
acid, i.e. where T is carboxyl. Where G and T of Compound IIIa are
respectively hydroxymethylene and alkoxycarbonyl, cleavage of the
ester group by exposure to Rhizopus oryzae (described in J. Amer.
Chem. Soc.; 95:1676 [1973]) or with a suitable esterase or lipase
(described in U.S. Pat. No. 3,769,166 and German Patent application
No. 2,242,792) yields the corresponding acid, i.e. where T is
carboxyl.
Treatment of Compounds IIIa or IIIe where T is carboxyl or
alkoxycarbonyl group, with a suitable carbonyl protecting group
followed by reduction and treatment with nitrous acid yields the
corresponding primary alcohol, i.e. where T is hydroxymethyl
(described in U.S. Pat. No. 3,636,120). Suitable carbonyl
protecting groups include lower alkoxyamines, semicarbazide or
thiosemicarbazides. Suitable reducing agents include lithium
aluminum hydride, lithium borohydride, and diisobutyl aluminum
hydride.
Non-toxic, pharmacologically acceptable salts of Compound III can
be prepared by neutralization of III, where T is carboxyl, with an
equivalent or an excess amount of the corresponding non-toxic
salt-forming organic or inorganic base. The salts are prepared by
procedures which are well-known in the art. Suitable salts include
sodium, potassium, ammonium and the like. The salts may be isolated
by lyophilization of the resulting mixture, or by filtration if
sufficiently insoluble, or by similar well-known techniques.
All compounds of this invention can be isolated from reaction
mixtures and purified by well-known organic chemistry procedures.
For example, the compounds can be isolated by dilution of the
reaction mixture with water, extraction with a water-immiscible
solvent such as benzene, cyclohexane, ether, ethyl acetate,
methylene chloride, toluene and the like; chromatography;
distillation or a combination of these procedures. Purification of
these compounds can be accomplished by the methods which are
well-known in the art for the purification of prostaglandins,
lipids, fatty acids, and fatty esters. For example, such methods as
reverse phase partition chromatography; counter-current
distribution; adsorption chromatography on acid washed magnesium
silicate, neutral or acid washed silica gel, alumina or silicic
acid; preparative paper chromatography; preparative thin layer
chromatography; high pressure liquid-liquid chromatography;
gas-liquid chromatography; and combinations thereof can be used to
purify the compounds produced by the processes of this
invention.
The starting reactants used in the above procedures are well-known
or easily prepared by known methods. For instance, in the reaction
sequence depicted in Table A, Compound V, i.e. metallic lithium or
lower alkyl lithium such as t-butyllithium, sec-butyllithium or
n-butyllithium are commercially available or prepared by well-known
organic chemistry methods. Examples of Compound VI, i.e. copper(I)
complexes, include: [hexamethylphosphorous triamide].sub.2
copper(I) pentyne (preparation described in J. Amer. Chem. Soc.;
94:7210 [1972]); and J. Org. Chem.; 31:4071 [1966]);
tri-n-butylphosphine-copper(I) iodide (preparation described in
Inor. Synth.; 7:9 [1963]); hexamethylphosphorus triamidecopper(I)
iodide (preparation described in Prostaglandins; 7:387 [1974]);
copper(I) thiophenolate (preparation described in Synthesis, 662
[1974]) and the like. Examples of Compound VII which are employed
in the synthesis of III, where T is hydroxymethyl or
acetoxymethylene radical, include:
1-(tetrahydropyran-2-yloxy)-7-(5-oxocyclopent-1-enyl) heptane
(preparation described in Tet. Let., 24:2435 [1972]);
1-(tetrahydropyran-2-yloxy)-7-(5-oxocyclopent-1-enyl) hept-5Z-ene;
1-(tetrahydropyran-2-yloxy)-6-(5-oxocyclopent-1-enyl) hexane;
1-(tetrahydropyran-2-yloxy)-6-(5-oxocyclopent-1-enyl) hex-4Z-ene;
1-(tetrahydropyan-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-
1-enyl] heptane;
1-(tetrahydorpyran-2-yloxy)-7-[3R-tetrahydropyran-2-yloxy)-5-oxocyclopent-
1-enyl] hept-5Z-ene;
1-(tetrahydropyran-2-yloxy)-6-[3R-tetrahydropyran-2-yloxy)-5-oxocyclopent-
1-enyl] hexane;
1-tetrahydropyran-2-yloxy)-6-[3R-tetrahydropyran-2-yloxy)-5-oxocyclopent-1
-enyl] hex-4Z-ene;
1-(tetrahydropyran-2-yloxy)-7-(6-oxocyclohex-1-enyl) heptane;
1-(tetrahydropyran-2-yloxy)-7-(6-oxocyclohex-1-enyl) hept-5Z-ene;
1-(tetrahydropyran-2-yloxy)-6-(6-oxocyclohex-1-enyl) hexane; and
1-(tetrahydropyran-2-yloxy)-6-(6-oxocyclohex-1-enyl)
hex-4Z-ene.
Examples of Compound VII which are employed in the synthesis of
III, where T is alkoxycrbonyl, carboxyl or salts thereof, include
methyl 7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
heptanoate (preparation described in J. Amer. Chem. Soc.; 95:1676
[1973]); methyl 7-(6-oxocyclohex-1-enyl)hept-5Z-enoate; methyl
7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
hept-5Z-enoate (preparation described in Tet. Let., 2313 [1973]);
methyl 7-[3S-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
heptanoate (preparation described in J. Amer. Chem. Soc.; 97:865
[1975]); and methyl
7-[3S-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
hept-5Z-enoate (preparation described in J. Amer. Chem. Soc.;
97:865 [1975]).
The examples of Compound VII disclosed above which are employed in
the synthesis of III where T is a hydroxymethyl or acetoxymethylene
radical, can be prepared from well-known materials by various
methods including the following: ##STR36## wherein G is a
methylene, .alpha.- or .beta.-hydroxymethylene radical; J is a
methylene or ethylene radical such that J is ethylene only when G
is methylene; T.sub.2 is an alkoxycarbonyl having from 1 to 3
carbon atoms inclusive in the alkoxy chain; A is an acid-labile
hydroxyl-protecting group; G' is methylene, .alpha.- or
.beta.-hydroxymethylene radical protected with an acid-labile
hydroxyl-protecting group-A; and Q and p are as defined above. In
IX.fwdarw.X, Compound IX is reacted with hydroxylamine to form the
corresponding oxime-protected carbonyl, Compound X, using
conditions which are well-known in the art (see U.S. Pat. No.
3,636,120 and Australian Patent No. 5,108,173). In X.fwdarw.XI,
Compound X is reacted with a suitable reducing agent such as
lithium aluminum hydride, or the like, at a temperature below about
30.degree. C. to reduce the ester or carboxyl group at T to the
corresponding alcohol, Compound XI (where T is hydroxymethyl). In
XI.fwdarw.XII, Compound XI is reacted with nitrous acid at a
temperature of about -10.degree. to about 50.degree. C. to remove
the oxime protecting group and to regenerate the carbonyl. The
nitrous acid is formed by adding an aqueous solution of an alkali
metal or alkaline earth metal nitrite, such as sodium nitrite, to a
liquid alkonoic acid such as acetic or propionic acid. In
XII.fwdarw.VII, Compound XII is reacted with a suitable acid-labile
hydroxyl-protecting groups (A) such as dihydropyran or ethylvinyl
ether in the presence of an acid catalyst such as p-toluensulfonic
acid, 98% sulfuric acid or phosphorus oxychloride to form Compound
VII and the product is isolated by standard procedures.
Compound IV of Table A is prepared according to the reaction
sequence depicted in Tables B and C. Examples of Compounds having
Formula IV which are used in the reaction
TABLE B
__________________________________________________________________________
##STR37##
__________________________________________________________________________
IV.fwdarw.III include:
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethyl-1-methylcyclobutyl)-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-(1-methylcyclobutyl)-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-(1-butylcyclobutyl)-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-[3-(3-cyclohexylpropyl)cyclobutyl]-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-[3-(cyclobutylmethyl)cyclobutyl]-1E-propene;
1-iodo-3-(1-ethoxyethoxy)-3-[3-(5-cyclododecylpentyl)cyclobutyl]-1E-propen
e,
1-iodo-3-(1-ethoxyethoxy)-3-[3-ethyl-3-(3-cyclohexylpropyl)cyclobutyl]-1E-
propene and
1-iodo-3-(1-ethoxyethoxy)-3-(3-cyclobutyl-cyclobutyl)-1E-propene.
The synthesis of Compound IV from the corresponding cyclobutane
carboxylic acid IVa can be accomplished via the reaction sequence
of Table B and C by well-known organic chemistry procedures.
Using the Reaction sequence, IVa.fwdarw.IVb.fwdarw.IVf, depicted in
Table B, the cyclobutane carboxylic acid is converted into the
.beta.-chlorovinyl ketone IVf where M.sub.1 is hydrogen. In
IVa.fwdarw.IVb, the cyclobutane carboxylic acid is converted to the
acid chloride IVb using an acid chloride forming reagent such as
thionyl chloride, oxalyl chloride, phosphorus trichloride and the
like as described in Fieser & Fieser, Reagents for Organic
Synthesis, I:1158, J. Wiley & Sons, Inc. (1967). In
IVb.fwdarw.IVf, the acid chloride IVb is reacted with acetylene in
an inert solvent such as carbon tetrachloride, methylene chloride
or the like, in the presence of a Lewis acid such as aluminum
chloride, stannic chloride or the like to produce the
.beta.-chlorovinyl ketone IVf as described in Chem. Rev., 161
(1965) and Org. Synth., Coll. Vol. IV:186, J. Wiley & Sons,
Inc. (1963).
TABLE C ______________________________________ ##STR38## IVf
##STR39## IVg ##STR40## IVh ##STR41## IV
______________________________________
Using the reaction sequence,
IVa.fwdarw.IVc.fwdarw.IVd.fwdarw.IVe.fwdarw.IVf, depicted in Table
B, the cyclobutanecarboxylic acid is converted into the
.beta.-chlorovinyl ketone IVf where M.sub.1 is a lower alkyl of 1
to 5 carbon atoms. In IVa.fwdarw.IVc, the cyclobutanecarboxylic
acid is converted to the lower alkyl substituted M.sub.1
cyclobutanecarboxylic acid IVc using lithium diisopropylamine in an
aprotic solvent such as tetrahydrofuran followed by treatment with
a lower alkyl halide as described in J. Amer. Chem. Soc., 92:1397
(1970). Lithium diisopropyl amine can be generated by mixing
n-butyllithium with diisporopylamine in tetrahydrofuran. Sutitable
lower alkyl halides include methyl iodide, ethyl bromide,
1-iodopropane, 2-iodopropane, 1-bromopropane, 2-bromopropane,
1-iodobutane, 1-bromopentane and 2-bromopentane. In IVc.fwdarw.IVd,
the lower alkyl substituted M.sub.1 cyclobutanecarboxylic acid IVc
is converted to the corresponding methyl ketone IVd using methyl
lithium as described in J. Amer. Chem. Soc., 55:1258 (1933). In
IVd.fwdarw.IVe, the lower alkyl substituted cyclobutyl methyl
ketone (IVd) is converted to the corresponding hydroxy vinyl ketone
(IVe) by treatment of a mixture of compound IVd and methyl formate
with sodium hydride followed by treatment of the enolate in ether
with hydrochloric acid to obtain the free enol as described in Org.
Syn. Coll. Vol. 4:536 (1963) and J. Amer. Chem. Soc., 76:552
(1954). In IVe.fwdarw.IVf, compound IVe is converted into the
.beta.-chlorovinyl ketone IVf using a chloride forming reagent,
such as thionyl chloride in benzene as described in Chem. Abstr.,
49:10830f (1955).
In IVf.fwdarw.IVg (Table C), the .beta.-chlorovinyl ketone (IVf) is
converted to the corresponding .beta.-iodo- or .beta.-bromo-vinyl
ketone IVg, where X is an iodo or bromo radical, using a soluble
salt, such as sodium iodide, sodium bromide, lithium bromide or the
like in a polar inert solvent, such as acetone, acetonitrite or the
like, as described in J. Amer. Chem. Soc., 94:7210 (1972). In
IVg.fwdarw.IVh, compound IVg is reduced to the corresponding
.beta.-iodo- or .beta.-bromo-vinyl alcohol using a suitable
reducing agent, such as sodium borohydride in alcohol solvent or
lithium aluminum hydride in ether solvent as described in J. Amer.
Chem. Soc., 94:7210 (1972). In IVh.fwdarw.IV, compound IVh is
treated with a suitable hydroxyl-protecting agent (A) such as
dihydropyran or ethylvinyl ether in the presence of an acid
catalyst such as p-toluenesulfonic acid, 98% sulfuric acid or
phosphorus oxychloride; or a trialkylsilylchloride, such as
trimethylsilychloride or t-butyldimethylsilylchloride, or
triphenylmethylbromide in the presence of a basic catalyst such as
triethylamine or imidazole. Any hydroxyl-protecting group that is
removable under mildly acid conditions and is stable to
alkyllithium and alkylcopper(I) reagents can also be suitably used,
see J. Org. Chem., 37:1947 (1972).
Examples of the corresponding cyclobutanecarboxylic acids having
formula IVa include: cyclobutanecarboxylic acid;
3-methylcyclobutanecarboxylic acid; 3-ethylcyclobutanecarboxylic
acid; 3-propylcyclobutanecarboxylic acid;
3-butylcyclobutanecarboxylic acid; 3-pentylcylcobutanecarboxylic
acid; 3-(3-cyclohexylpropyl)cyclobutanecarboxylic acid;
3-(cyclobutylmethyl)cyclobutanecarboxylic acid;
3-(5-cyclododecylpentyl)cyclobutane;
3-ethyl-3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid,
3-cyclobutylcyclobutane-1-carboxylic acid and the like. The
cyclobutanecarboxylic acid of Formula IVa are either commercially
available or are prepared by well-known organic chemistry
techniques from commercially available materials. One such
procedure is depicted by the reaction sequence of Table D.
TABLE D
__________________________________________________________________________
##STR42## ##STR43##
__________________________________________________________________________
In Table D, the reaction steps IVq to IVz are described in Justus
Liebigs Ann. Chem., 685:74 (1965) and J. Org. Chem., 31:4069
(1966). In IVq.fwdarw.IVr, a carboxylic acid IVq, where M is
hydrogen or --(CH.sub.2).sub.n M.sub.4 and n is zero or an integer
from 1 to 4 and M.sub.4 is as defined above, is reduced to the
corresponding alcohol IVr, where M is as defined above, using a
suitable reducing agent such as lithium aluminum hydride (see
Fieser & Fieser, Reagents for Organic Synthesis, 1:581, J.
Wiley & Sons (1967). In IVr.fwdarw.IVs, the alcohol IVr is
treated with p-toluensulfonyl chloride in pyridine to form the
tosylate IVs (see Fieser & Fieser, Reagents for Organic
Synthesis, 1:1179, J. Wiley & Sons, [1967]). In IVs.fwdarw.IVt,
the tosylate IVs is treated with the sodium enolate of
diethylmalonate, prepared from sodium and diethylmalonate in xylene
(see Organic Reactions, 9:107 [1957]) to form the diethyl alkylated
malonate IVt. In IVt.fwdarw.IVw, the diethyl alkylated malonate IVt
is reduced to the corresponding bis-hydroxymethyl derivative IVw
using lithium aluminum hydride (see Modern Synthetic Reactions, 2nd
Ed., 84, W. A. Benjamin, Inc. [1972]). Alternatively, in
IVt.fwdarw.IVu, the diethyl alkylated malonate IVt is alkylated by
treatment of the sodium enolate of diethyl alkylated malonate IVt
with an alkylating agent such as a lower alkyl-tosylate, halide,
carbonate, sulfonate or the like in xylene to form the diethyl
dialkylated malonate IVu (see Organic Reactions, 9:107 [1957]). In
IVu.fwdarw.IVw, the diethyl dialkylated malonate IVu is reduced as
in IVt.fwdarw.IVw above, to the corresponding bis-hydroxymethyl
derivative IVw using a reducing agent such as lithium aluminum
hydride. In IVw.fwdarw.IVx, the bis-hydroxymethyl derivative IVw is
converted to the ditosylate IVx by treatment with p-toluensulfonyl
chloride as above. In IVx.fwdarw.IVy, the ditosylate IVx is
converted to the 3-substituted cyclobutane-1,1-diethylester IVy by
treatment with the sodium enolate of diethyl malonate as above. In
IVy.fwdarw.IVz, compound IVy is hydrolyzed in a suitable base to
yield the cyclobutane 1,1-dicarboxylic acid IVz. In IVz.fwdarw.IVa,
the cyclobutane 1,1-dicarboxylic acid is decarboxylated by heating
(see Modern Synthetic Reactions, 2nd Ed.; 513, W. A. Benjamin, Inc.
[1972]) to produce the cyclobutanecarboxylic acid IVa.
In Table D, where M.sub.2 is --(CH.sub.2).sub.n -M.sub.4 and n is
0, then the reaction step IVs to IVt is preferrably accomplished by
reacting the tosylate IVs with sodium cyanide in Dimethylsulfoxide
to form the mitrile-M CN (IVs.sub.1) (see J. Amer. Chem. Soc., 92,
336 [1970]). The nitrile IVs.sub.1 is then treated with aqueous
ethanol and aqueous potassium hydroxide to form the acid-M CO.sub.2
H (IVs.sub.2) (see J. Amer. Chem. Soc., 98, 222 [1976]. The acid
IVs.sub.2 is then treated with sulfuric acid and absolute ethanol
in a simple Fischer esterification step to form the ester M
CO.sub.2 Et (IVs.sub.3). The ester IVs.sub.3 is then treated with
ethyl chloroformate and lithium dissopropylamide to form the
diethyl alkylated malonate (IVt) (see J. Org. Chem., 39, 2114
[1974]).
The compounds represented by Formula III inhibit aggregation of
human platelets in vitro as demonstrated in the following Example
17. It is that feature which distinguishes the compounds of this
invention over the natural prostaglandins. Of the natural
prostaglandins, only PGE.sub.1 displays a similar activity. The
prostaglandin analogs of this invention also stimulate in vitro and
in vivo smooth muscle preparations derived from a variety of
tissues and organs of experimental animals. In particular,
preferred prostaglandin analogs of this invention also exhibit
selective gastric antisecretory and bronchodilatory activity. It
has been found that the compounds of this invention exhibit fewer
undesirable side activities than the natural prostaglandins. Such
smooth muscle and in vivo assays are widely utilized to determine
the activity of natural prostaglandins as well as prostaglandin
analogs (Bundy et al., Ann. N.Y. Acad. Sci., 180:76 [1961];
Bergstrom et al., Pharmacal. Revs., 20:1 [1968]). Details of the
activity of selected compounds having Formula III are presented in
Example 43 below.
In order to further illustrate the novel aspects of the present
invention, the following examples are presented. It should be
recognized that these examples are provided by way of illustration
only and are not intended to limit in any way the invention
disclosed herein.
EXAMPLE 1
This example illustrates the preparation of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene.
A. Preparation of 2-Ethylpropan-1,3-diol
Lithium aluminum hydride (15.5 g, 0.4 mole) was slurried in 600 ml
of dry ether (distilled from benzophenone-ketyl, generated in situ
from sodium and benzophenone). The slurry was cooled in an
ice-water bath and then a solution of 37.6 g (0.2 mole) of diethyl
ethylmalonate (Aldrich Chemical Company; Beilstein 2: 644) in 100
ml of dry ether was added thereto. The mixture was heated to reflux
for 3 hr and then it was cooled in an ice-water bath. Ethyl acetate
(52 ml) was carefully added, followed by water (15.5 ml), followed
by the addition of 15.5 ml of 15% aqueous sodium hydroxide solution
and then 31 ml of water. This mixture was filtered and the solvents
were removed from the filtrate by evaporation in vacuo to yield
12.3 g of the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.0(6H,multiplet) and 3.1 to
3.9 ppm (6H,multiplet).
B. Preparation of 2-Ethylpropyl-1,3-ditosylate
A mixture containing 12.3 g (0.118 mole) of 2-ethylpropan-1,3-diol
(prepared in 1A) and 350 ml of dry pyridine (distilled from calcium
hydride) was prepared and cooled in an ice-water-salt bath. To this
mixture there was then added 67.5 g (0.354 mole) of
p-toluenesulfonyl chloride and the mixture was stirred for 3 hr at
-15.degree. C. This mixture was then poured into 3 l of ice-cold 6
N hydrochloric acid. The resultant mixture was extracted with 1800
ml (3.times.600 ml) of ether. The ether extracts were combined and
dried over anhydrous potassium carbonate-sodium sulfate, filtered
and the solvent removed in vacuo to yield 48.1 g of the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8(3H,triplet,J=6 Hz), 1.35
(3H,triplet,J=6 Hz), 1.9(1H,quart), 2.48(6H,singlet),
3.9(4H,doublet,J=6 Hz), and 7.5 ppm (8H,AB,J=10 Hz).
C. Preparation of 3-Ethyl-1,1-dicarbethoxycyclobutane
Sodium metal (7.6 g, 0.33 g/atom) was dispersed in 50 ml of dry
xylene (distilled from sodium hydride) by heating to 130.degree. C.
with rapid stirring. Dry xylene (168 ml) and 47.8 g (45.2 ml, 0.298
mole) of diethyl malonate were then added thereto and the mixture
was allowed to react at 120.degree. C. To the resultant mixture
there was then added 48.1 g (0.116 mole) of
2-ethyl-propyl-1,3-ditosylate (prepared in 1B) dissolved in 120 ml
of dry xylene. This reaction mixture was heated to about
150.degree. C. and stirred for 18 hr. The mixture was cooled and
poured into 500 ml of water and extracted with 600 ml (3.times.300
ml) of ether. The aqueous material was made acidic with 10% aqueous
HCl and then extracted with 600 ml (2.times.300 ml) of ether. The
combined ether extract was washed with 200 ml of saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered
and the solvent was removed in vacuo. Distillation of the product
at reduced pressure yielded 7.0 g of the title compound having the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6(3H,triplet,J=7 Hz), 1.2
(6H,triplet,J=8 Hz), 1.9-2.8(7H,multiplet), and 4.3 ppm
(4H,overlapping quartets,J=8 Hz).
D. Preparation of 3-Ethylcyclobutane-1,1-dicarboxylic acid
A solution of 7.0 g (0.031 mole) of
3-ethyl-1,1-dicarbethoxycyclobutane (prepared in 1C) dissolved in 7
ml of absolute ethanol was prepared. To this solution there was
added 6.87 g (0.123 mole) of potassium hydroxide dissolved in 76 ml
of absolute ethanol and the mixture was heated to reflux with
stirring for 1.5 hr. The mixture was then filtered and the filter
cake was washed with 10 ml of absolute ethanol and 75 ml of ether.
The resulting filter cake was dissolved in 30 ml of ice water and
acidified with 36 ml of 50% aqueous sulfuric acid. The resulting
mixture was cooled, filtered and dried to yield 4.5 g of the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.85(3H,triplet,J=7 Hz),
1.1-1.7(3H,multiplet) and 1.8-2.8 ppm(4H,multiplet).
E. Preparation of 3-Ethylcyclobutane carboxylic acid
The 3-ethylcyclobutane-1,1-dicarboxylic acid (4.5 g, 0.026 mole;
prepared in 1D) was decarboxylated by heating the compound to
190.degree. C. for about 15 min. Frothing accompanied this
decarboxylation and when this ceased the mixture was cooled to
yield ca. 3.3 g of the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8(3H,triplet,J=7 Hz),
1.1-3.4(11H,multiplet), and 12.3 ppm(1H,broad singlet).
F. Preparation of 3-Ethylcyclobutanecarboxylic acid chloride
A mixture of 3.3 g (0.027 mole) of 3-ethylcyclobutanecarboxylic
acid (prepared in 1E) and 9.4 g (5.7 ml, 0.080 mole) of thionyl
chloride was prepared and allowed to stir at room temperature for
about 15 hr. Excess thionyl chloride was removed by distillation at
atmospheric pressure. The residue was distilled at reduced pressure
to yield 2.4 g of the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8(3H,triplet,J=7 Hz),
1.1-1.6(3H,multiplet) and 1.8-2.8 ppm(4H,multiplet).
G. Preparation of 3-Ethylcyclobutyl-trans-.beta.-chlorovinyl
ketone
A solution of 8.4 g (0.058 mole) of 3-ethylcyclobutanecarboxylic
acid chloride (prepared as in 1E) in 10 ml of carbon tetrachloride
was added, under an acetylene atmosphere, to 9.7 g (0.072 mole) of
anhydrous aluminum chloride slurried in 100 ml of carbon
tetrachloride while being cooled in an ice-water bath. Acetylene
was bubbled through the stirred mixture for 4 hours. The resultant
mixture was then poured into 150 ml of ice and 150 ml of saturated
aqueous sodium chloride. The phases which formed were separated and
the aqueous phase was extracted with 300 ml (2.times.150 ml) of
ether. The combined ether extracts were successively washed with
100 ml of 10% aqueous hydrochloric acid, 100 ml of saturated
aqueous sodium bicarbonate and 100 ml of saturated aqueous sodium
chloride. The resultant ether extract was dried over anhydrous
magnesium sulfate, filtered and the solvent was removed in vacuo.
The residue was chromatographed on silica gel 60 (0.063-0.2 mm,
70-230 mesh, ASTM) using benzene as the eluant to yield 3.92 g of
the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7(3H,triplet,J=8 Hz),
1.0-2.7(7H,multiplet)3.0(1H,multiplet), 6.4(1H,doublet, J=16 Hz),
and 7.3 ppm(1H,doublet,J=16 Hz).
H. Preparation of 3-Ethylcyclobutyl-trans-.beta.-iodovinyl
ketone
A mixture containing 3.92 g (0.0228 mole) of
3-ethylclobutyl-trans-.beta.-chlorovinyl ketone (prepared in 1F),
and 13.6 g (0.091 mole) of sodium iodide and 70 ml of dry acetone
(distilled from anhydrous potassium carbonate) was prepared and
heated at reflux temperature with stirring for 18 hr. The mixture
was cooled and the solvent was removed in vacuo. The solid residue
was taken up in 50 ml of water and the products extracted with 150
ml (3.times.50 ml) of ether. The combined ether extract was
successively washed with 30 ml of aqueous sodium thiosulfate
solution and 30 ml of saturated aqueous sodium chloride. The washed
ether extract was then dried over anhydrous magnesium sulfate,
filtered and the solvent was removed in vacuo to yield 5.3 g of the
title compound having the following characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8(3H,triplet,J=8 Hz),
1.0-2.6(7H,multiplet), 3.1(1H,multiplet), 7.0 (1H,doublet, J=15
Hz), and 7.6 ppm (1H,doublet,J=15 Hz).
I. Preparation of
1-(3-Ethylcyclobutyl)-trans-3-iodoprop-2-en-1-ol
A solution of 5.3 g (0.02 mole) of
3-ethylcyclobutyl-trans-.beta.-iodovinyl ketone (prepared in 1H)
dissolved in 200 ml of absolute ethanol was prepared and cooled in
a salt-ice-water bath. Sodium borohydride (1.51 g, 0.04 mole) was
slurried in 50 ml of absolute ethanol and added to the cooled
solution. The resulting mixture was allowed to stir for 1 hr at
0.degree. C. The solvent was removed in vacuo and the residue was
taken up in 100 ml of water. The aqueous mixture was then extracted
with 150 ml (3.times.50 ml) of ether. The combined ether extract
was washed with 50 ml of saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered, and the solvent removed
in vacuo to yield 4.8 g of the title compound having the following
physical characteristics:
Analysis--NMR (CDCl.sub.3): .delta.0.8(3H,triplet,J=8 Hz),
1.0-2.3(3H,multiplet), 4.0(2H,multiplet), and 6.1-6.7 ppm
(2H,multiplet).
J. Preparation of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene
A mixture containing 4.8 g (0.018 mole) of
1-(3-ethylcyclobutyl)-trans-3-iodoprop-2-en-1-ol (prepared in 1I)
and 38.2 g (50 ml, 0.51 mole) of ethylvinyl ether (Aldrich Chemical
Company; Beilstein 1:433) was prepared. One drop of phosphorus
oxychloride was added thereto and the mixture was allowed to stir
for about 15 hr at room temperature. The mixture was poured into 50
ml of saturated aqueous sodium bicarbonate and the products were
extracted with 150 ml (3.times.50 ml) of ether. The combined ether
extract was washed with 50 ml of saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and the solvent
was removed in vacuo. The residue was chromatographed on silica gel
60 (0.063-0.2 mm, 70-230 mesh, ASTM) using chloroform as the eluant
to yield 4.2 g of the title compound having the following physical
characteristics:
Analysis--NMR (CDCl.sub.3): .delta.0.7 (3H,triplet,J=8 Hz), 1.0-1.5
(6H,multiplet), 1.5-2.5 (7H,multiplet), 3.5 (3H, multiplet), 4.5
(1H,quartet,J=6 Hz) and 6.1-6.5 ppm (2H,multiplet).
EXAMPLE 2
A. Preparation of 1-Methyl-3-ethylcyclobutanecarboxylic acid
A solution of 19.9 ml (140 mmol) of dry diisopropylamine in 100 ml
of dry tetrahydrofuran was stirred in under an argon atmosphere and
63.6 ml (140 mmol) of a solution of n-butyllithium (2.2 M) in
hexane was added dropwise thereto while maintaining the temperature
below about 5.degree. C. The resultant mixture was then stirred for
15 min with ice-bath cooling. A solution of 8.2 g (64 mmol) of
3-ethylcyclobutanecarboxlic acid (prepared in Example 1E) in 15 ml
of dry tetrahydrofuran was added dropwise to the reaction mixture
and stirred with cooling for 15 min. Methyl iodide (4.36 ml, 70
mmol) was added to the reaction mixture dropwise and the resultant
mixture was stirred without cooling for 2 hr. The mixture was then
stirred with ice-methanol bath cooling as 10% hydrochloric acid was
added dropwise until the resultant aqueous phase was acidic (about
25 ml was used). The aqueous phase was separated and extracted
twice with ether. The combined ether extract was dried over
anhydrous magnesium sulfate and the solvent removed in vacuo to
yield 10 g of the title compound having the following physical
characteristics:
Analysis--NMR (CDCl.sub.3): .delta.0.8 (3H,broad triplet,J=7.0 Hz),
1.0 to 3.0 (7H,multiplet), 1.37 and 1.47 (3H,total two singlets,
two isomers), 10.6 ppm (1H,broad singlet).
B. Preparation of 1-Methylcyclobutanecarboxylic acid
The title compound was prepared as in Example 2A by replacing
3-ethylcyclobutanecarboxylic acid with cyclobutanecarboxylic acid
(Aldrich Chemical Company; Beilstein: 9,5). The resultant product
had the following physical characteristics:
Analysis--NMR (CDCl.sub.3): .delta.1.43 (3H,singlet), 1.5-2.7
(6H,multiplet), 12.5 ppm (1H,singlet); IR(CHCl.sub.3).nu.: 660,
730, 760, 1210, 1700 and 2400 to 3300 cm.sup.-1 (broad).
C. Preparation of 1-Butylcyclobutanecarboxylic acid
The title compound was prepared as in Example 2A by replacing
3-ethylcyclobutanecarboxylic acid and methyl iodide respectively
with cyclobutanecarboxylic acid and 1-iodobutane (Aldrich Chemical
Company; Beilstein 1: 123). The resultant product had the following
physical characterisics:
Analysis--NMR(CDCl.sub.3): .delta.0.92 (3H,broad triplet,J=6 Hz),
1.0 to 2.8 (12H,multiplet), 12.3 ppm (1H, broad singlet)
IR(CHCl.sub.3).nu.: 1250, 1695 and 2400 to 3500 cm.sup.-1
(broad).
EXAMPLE 3
A. Preparation of (1-Methyl-3-ethylcyclobutyl) methyl ketone
A solution of 5.0 g (35 mmol) of
1-methyl-(3-ethyl)-cyclobutanecarboxylic acid (prepared in Example
2A) in 35 ml of dry ether was stirred with ice-bath cooling under
an argon atmosphere and 40 ml of a 2 M solution of methyllithuim in
ether was added thereto. The resultant mixture was stirred without
cooling for 3 hr. This mixture was then quenched by pouring the
mixture into a vigorously stirred solution of 30 ml of methanol and
70 ml of water. The aqueous phase was separated and extracted twice
with ether. The combined ether extract was dried over anhydrous
magnesium sulfate and evaporated. The residue was distilled at
reduced pressure to yield 2.5 g of the title compound having the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.79 (3H,broad triplet, J=6.5
Hz), 1.33 and 1.38 (3H,total,two singlet, isomers), 1.0 to 2.8
(7H,multiplet), 2.07 and 2.16 ppm (3H, total, two singlets,
isomers).
B. Preparation of (1-Methylcyclobutyl) methyl ketone
The title compound was prepared according to the procedure of
Example 3A by replacing 1-methyl-3-ethylcyclobutanecarboxylic acid
with 1-methylcyclobutanecarboxylic acid (prepared in Example 2B).
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.36 (3H,singlet), 2.09 (3H,
singlet), 1.4 to 2.6 ppm (6H,multiplet); IR(CHCl.sub.3).nu.: 1120,
1350, 1700, 2870 and 2960 cm.sup.-1.
C. Preparation of (1-Butylcyclobutyl) methyl ketone
The title compound was prepared according to the procedure of
Example 3A by replacing 1-methyl-3-ethylcyclobutanecarboxylic acid
with 1-butylcyclobutanecarboxylic acid (prepared in Example 2C).
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.90 (3H,broad triplet,J=6 Hz),
1.0 to 2.8 (12H, multiplet), 2.07 (3H, singlet);
IR(CHCl.sub.3).nu.: 1130, 1360, 1695, 2860, 2940 and 2960
cm.sup.-1.
EXAMPLE 4
A. Preparation of
1-Hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one
Sodium hydride (1.25 g of 50% mineral oil dispersion, 50 mmol) was
washed with dry hexane and then stirred under an argon atmosphere
with 12.5 ml of dry ether. A solution of 5 ml of methyl formate and
2.4 g of (1-methyl-3-ethylcyclobutyl) methyl ketone (prepared in
Example 3A) in 5 ml of ether was then added to the reaction mixture
along with about 0.5 ml of methanol. As a voluminous precipitate
formed, sufficient ether was added to make the reaction mixture
more easily stirred. The resultant mixture was stirred for 1 hr and
then quenched by the addition of water. The ether phase was
separated and extracted three times with 1 M sodium hydroxide. The
combined aqueous extraction phases were acidified with concentrated
hydrochloric acid and extracted three times with ether. The
combined ether extract was evaporated in vacuo. Traces of water
were removed by twice addition of benzene which was removed by
evaporation in vacuo. The title compound had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8 (3H,broad triplet, J=6.5 Hz),
1.3 and 1.37 (3H total,two singlets, isomers), 1.0 to 2.8
(7H,multiplet), 5.57 and 5.73 (1H total,two doublets, J=4.5
Hz,isomer), 7.5 (1H, singlet), 8.00 and 8.04 ppm (1H,total, two
doublets, J=4.5 Hz,isomers).
B. Preparation of
1-Hydroxy-3-(1-methylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of
Example 4A by replacing (1-methyl-3-ethylcyclobutyl) methyl ketone
with (1-methylcyclobutyl) methyl ketone prepared in Example 3B. The
resultant product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.40 (3H,singlet), 1.5 to 2.7
(6H,multiplet), 5.61 (1H,doublet,J=4.5 Hz), 7.45 (1H, singlet),
8.04 ppm (1H,doublet,J=4.5 Hz); IR(CHCl.sub.3).nu.: 660, 740, 1075,
1255, 1595, 1635, 2880 and 2970 cm.sup.-1.
C. Preparation of
1-Hydroxy-3-(1-butylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of
Example 4A by replacing (1-methyl-3-ethylcyclobutyl) methyl ketone
with (1-butylcyclobutyl) methyl ketone prepared in Example 3C. The
resultant product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.88 (3H,broad triplet, J=6 Hz),
1.0 to 2.8 (12H,multiplet), 5.62 (1H,doublet, J=4.5 Hz), 7.98
(1H,doublet,J=4.5 Hz), 7.8 ppm (1H,very broad singlet);
IR(CHCl.sub.3).nu.: 1080, 1250, 1450, 1590, 1630, 2860, 2930 and
2960 cm.sup.-1.
EXAMPLE 5
A. Preparation of
trans-1-Chloro-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one
A solution of 5.8 g of
1-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one (prepared
in Example 4A) in 100 ml of benzene was stirred under an argon
atmosphere and 7 ml of thionyl chloride in 10 ml of benzene was
added dropwise. The resulting solution was stirred for about 15 hr.
Excess solvent was removed by distillation at atmospheric pressure
and the residue was then distilled in vacuo to yield 4.2 g of the
title compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H,broad triplet,J=6.5 Hz),
1.0 to 3.0 (7H,multiplet), 1.33 and 1.40 (3H total,
singlet,isomers), 6.72 and 6.87 (1H total,two doublet, J=13.5
Hz,isomers), 7.48 and 7.51 ppm (1H total, two doublets, J=13.5
Hz).
B. Preparation of
trans-1-Chloro-3-(1-methylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of
Example 5A by replacing
1-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one with
1-hydroxy-3-(1-methylcyclobutyl)-prop-1-en-3-one prepared in
Example 4B. The resultant product had the following physical
characteristics:
Analysis--NMR (CDCl.sub.3): .delta.1.38 (3H,singlet), 1.5 to 2.7
(6H,multiplet), 6.73 (1H,doublet,J=12.5 Hz), 7.46 ppm
(1H,doublet,J=12.5 Hz); IR(CHCl.sub.3).nu.: 660, 760, 1210, 1590,
1710, 2880 and 2970 cm.sup.-1.
C. Preparation of
trans-1-chloro-3-(1-butylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of
Example 5A by replacing
1-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one with
1-hydroxy-3-(1-butylcyclobutyl)-prop-1-en-3-one prepared in Example
4C. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.88 (3H,broad triplet, J=6 Hz),
1.0 to 2.9 (12H,multiplet), 6.72 (1H,doublet, J=13.5 Hz), 7.48 ppm
(1H,doublet,J=13.5 Hz); IR(CHCl.sub.3).nu.: 940, 1085, 1590, 1690,
2860, 2940 and 2970 cm.sup.-1.
EXAMPLE 6
A. Preparation of
trans-1-iodo-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one
A solution of 4.2 g of
trans-1-chloro-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one
(prepared in Example 5A) and 10 g of anhydrous sodium iodide in 60
ml of acetone was refluxed with about 0.5 ml H.sub.2 SO.sub.4 for 4
hr under an argon atmosphere. The solvent was removed by
evaporation in vacuo. The residue was diluted with water and the
aqueous mixture was extracted several times with ether. The
combined ether extract was washed with aqueous sodium thiosulfate
solution and then dried over anhydrous magnesium sulfate and
evaporated in vacuo to yield 6.8 g of the title compound having the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H,broad triplet,J=6.5 Hz),
1.32 and 1.39 (3H total, two singlets,isomers), 1.0 to 2.8
(7H,multiplet), 7.32 and 7.45 (1H total, two doublets, J=14.5
Hz,isomers), 8.00 and 8.03 ppm (1H total, two doublets,J=14.5 Hz,
isomers).
B. Preparation of
trans-1-Iodo-3-(1-methylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of
Example 6A by replacing
trans-1-chloro-3(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one with
trans-1-chloro-3-(1-methylcyclobutyl)-prop-1-en-3-one prepared in
Example 5B. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.38 (3H,singlet, 1.5 to 2.7
(6H,multiplet), 7.36 (1H,doublet,J=15 Hz), 7.98 ppm
(1H,doublet,J=15 Hz); IR(CHCl.sub.3).nu.: 950, 1080, 1570, 1690,
2870 and 2960 cm.sup.-1.
C. Preparation of
trans-1-Iodo-3-(1-butylcyclobutyl)-prop-1-en-3-one
The title compound was prepared according to the procedure of 6A by
replacing
trans-1-chloro-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one with
trans-1-chloro-3-(1-butylcyclobutyl)-prop-1-en-3-one prepared in
Example 5C. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9 (3H,broad triplet,J6 Hz), 1.0
to 2.8 (12H,multiplet, 7.37 (1H,doublet,J=15 Hz), 8.02 ppm
(1H,doublet,J=15 Hz); IR(CHCl.sub.3).nu.: 940, 1080, 1565, 1685,
2870, 2940 and 2870 cm.sup.-1.
EXAMPLE 7
A. Preparation of
trans-1-Iodo-3-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-ene
The title compound was prepared according to Example 1I by
replacing 3-ethylcyclobutyl-trans-.beta.-iodovinyl ketone with
trans-1-iodo-3-(3-ethyl-1-methylcyclobutyl-prop-1-en-3-one
(prepared in Example 6A). The resultant product was purified by
chromatography on silica gel 60 using a chloroform elution and had
the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.78 (3H,broad triplet,J=6.5 Hz),
1.01 and 1.10 (3H total,two singlets,isomers), 1.0 to 2.7
(8H,multiplet), 4.0(1H,multiplet) and 6.15 to 6.95 ppm
(2H,multiplet).
B. Preparation of
trans-1-Iodo-3-hydroxy-3-(1-methylcyclobutyl)-prop-1-ene
The title compound was prepared according to the procedure of
Example 1I by replacing 3-ethylcyclobutyl-trans-.beta.-iodo-vinyl
ketone with trans-1-iodo-3-(1-methylcyclobutyl)-prop-1-en-3-one
prepared in Example 6B. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.10 (3H,singlet), 1.3 to 2.7
(6H,multiplet), 4.02(1H,doublet,J=5 Hz) and 6.2 to 7.2 ppm
(2H,multiplet); IR(CHCl.sub.3).nu.: 910, 1610, 2880, 2950, 3200 to
3600 (broad) and 3610 cm.sup.-1.
C. Preparation of
trans-1-Iodo-3-hydroxy-3-(1-butylcyclobutyl)-prop-1-ene
The title compound was prepared according to the procedure of
Example 1I by replacing 3-ethylcyclobutyl-trans-.beta.-iodo-vinyl
ketone with trans-1-iodo-3-(1-butylcyclobutyl)-prop-1-en-3-one
(prepared in Example 6C). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.92 (3H,broad triplet,J=5 Hz),
1.0 to 2.7 (12H,multiplet), 4.1 (1H,triplet,J=5 Hz), 6.43
(1H,doublet,J=14 Hz), 6.79 ppm (1H,doublet, J=14.5 Hz);
IR(CHCl.sub.3).nu.: 905, 950, 1610, 2870, 2940, 2970, 3200 to 3600
(broad) and 3605 cm.sup.-1.
EXAMPLE 8
A. Preparation of
1-Iodo-3-(1-ethoxyethoxy)-3-(3-ethyl-1-methylcyclobutyl-1E-propene
A solution of 2.25 g (8.0 mmol) of
trans-1-iodo-3-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-ene
(prepared in Example 7A) in 8.0 ml of dry ether was stirred under
an argon atmosphere and 1.2 ml of ethylvinylether was added thereto
followed by about 5 mg of toluenesulfonic acid. The resultant
solution was stirred under argon for 1.5 hr at 25.degree. C.
Saturated aqueous sodium bicarbonate was added to the reaction
mixture and the aqueous mixture was then extracted with ether. The
ether phase was separated and washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate and evaporated in
vacuo to yield 2.7 g of the title compound having the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8 (3H,broad triplet,J=6.5 Hz),
0.9 2.5(16H,multiplet), 3.7(3H,multiplet), 4.8 (1H, broad
quarter,J=5.3 Hz), 6.5 ppm (2H,multiplet); IR (CHCl.sub.3).nu.:
945, 1020, 1090, 1120, 1380, 1460, 1605, 2870, 2930 and 2960
cm.sup.-1.
B. Preparation of
1-Iodo-3-(1-ethoxyethoxy)-3-(1-methylcyclobutyl)-1E-propene
The title compound was prepared according to the procedure of
Example 8A by replacing
trans-1-iodo-3-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-ene
with trans-1-iodo-3-hydroxy-3-(1-methylcyclobutyl)-prop-1-ene
prepared in Example 7B. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.10 (3H,singlet), 1.0 to 2.4
(12H,multiplet), 3.4 to 4.2 (3H,multiplet), 4.77 (1H,multiplet),
6.2 to 6.8 ppm (2H,multiplet); IR (film).nu.: 945, 1015, 1095,
1130, 1380, 1605, 2870, 2930 and 2980 cm.sup.-1.
C. Preparation of
1-Iodo-3-(1-ethoxyethoxy)-3-(1-butylcyclobutyl)-1E-propene
The title compound was prepared according to the procedure of
Example 8A by replacing
trans-1-iodo-3-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-ene
with trans-1-iodo-3-hydroxy-3-(1-butylcyclobutyl)-prop-1-ene
prepared in Example 7C. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7 to 2.6 (21H,multiplet), 3.2
to 4.2(3H,multiplet), 4.8(1H,multiplet), 6.2 to 6.9 ppm
(2H,multiplet); IR(CHCl.sub.3).nu.: 950, 1020, 1095, 1125, 1385,
1610, 2870 and 2940 cm.sup.-1.
EXAMPLE 9
A. Preparation of 3-Cyclohexylpropan-1-ol
Lithium aluminum hydride (24.2 g, 0.64 mole) was slurried into 300
ml of dry ether (distilled from benzophenone ketyl, generated in
situ from sodium and benzophenone). The slurry was cooled in an
ice-water bath and a solution of 100 g (0.64 mole) of
3-cyclohexylpropionic acid (Bielstein 9:[2]13) in 250 ml of dry
ether was slowly added. The resultant mixture was heated to reflux
for 1 hr and then cooled in an ice-water bath. Ethyl acetate (100
ml) was slowly added to the mixture. This addition was followed by
the addition of 24.2 ml of water, 24.2 ml of 15% aqueous sodium
hydroxide solution and 72.6 ml of water. The mixture was filtered
and the solvent was removed in vacuo. Distillation of this mixture
at reduced pressure resulted in 71.6 g (78.7%) of pure
3-cyclohexylpropan-1-ol having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.1 (15H,multiplet) 3.63 ppm
(2H,triplet,J=6 Hz).
B. Preparation of Cyclobutylmethanol
The title compound was prepared according to the procedure of
Example 9A by reducing cyclobutanecarboxylic acid (Aldrich;
Bielstein 9:5) with lithium aluminum hydride in ether. The
resulting product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.9 (7H,multiplet) .delta.3.6
(2H,doublet,J-7 Hz) 3.9 ppm (1H,broad singlet).
C. Preparation of 5-Cyclododecylpentan-1-ol
i. 5-cyclododecylidenepentanoic acid
Dry dimethylsulfoxide (50 ml, distilled from calcium hydride) and
24.1 ml (0.06 mole) of the sodium salt of dimethylsulfoxide (2.49 M
in dimethylsulfoxide, Fieser and Fieser, "Reagents for Organic
Synthesis", 1:310 [1967]) were mixed together and cooled in an
ice-water bath. Then 13.29 g (0.03 mole) of (4-carboxybutyl)
triphenylphosphonium bromide (Aldrich Chemical Co.) was added
thereto and the mixture was stirred for 30 min. Cyclododecanone
(3.64 g, 0.02 mole; Aldrich Chemical Co.: Beilstein 7[2],36) was
dissolved in 10 ml of dry dimethylsulfoxide and added to the above
mixture and the mixture was stirred for 15 hr at room temperature.
The resulting mixture was then poured into 500 ml of water. This
aqueous mixture was extracted with 900 ml (3.times.300 ml) of
ether-ethyl acetate (1:1 V/V). The aqueous phase was acidified (pH
1 to 2) with 30 ml of concentrated hydrochloric acid. The aqueous
phase was then extracted with 900 ml (3.times.300 ml) of
ether-hexane (1:1 V/V). The ether-hexane extract was then dried
over anhydrous magnesium sulfate, filtered, and the solvent removed
in vacuo. The resultant product was recrystallized from
ethanol-water to yield 2.0 g (36.2%) of
5-cyclododecylidenepentanoic acid (mp 70.degree.-72.degree. C.)
having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.5 (28H,multiplet); 5.2(1H,
triplet,J=7 Hz); 10.0 ppm (1H,broad singlet).
ii. 5-Cyclododecylpentanoic acid
From Example 9Ci above, 0.276 g (0.001 mole) of 5-cyclododecylidene
pentanoic acid was dissolved in 30 ml of glacial acetic acid.
Platinum oxide (0.027 g) was added and the mixture was hydrogenated
on a sloping-manifold hydrogenation apparatus for 3 hr at room
temperature. The resultant mixture was then filtered through Celite
(diatomaceous earth). The solvent was removed in vacuo to yield
0.26 g (93.8%) of 5-cyclododecylpentanoic acid having the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.2 (31H, multiplet), 11.8
ppm (1H, broad singlet).
iii. 5-Cyclododecylpentan-1-ol
The title compound was prepared according to the procedure
described in Example 9A by reducing the 5-cyclododecylpentanoic
acid (9Cii above) with lithium aluminum hydride in ether. The
resultant product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.0 (31H, multiplet), 3.7
(2H, triplet, J=6 Hz), 4.1 ppm (1H, broad singlet).
EXAMPLE 10
A. Preparation of 3-Cyclohexylpropyl-1-tosylate
3-Cyclohexylpropan-1-ol (1.42 g, 0.01 mole; prepared according to
Example 9A) was mixed with 25 ml of freshly distilled pyridine
(distilled from calcium hydride). The mixture was cooled in an
ice-water bath and 3.80 g (0.02 mole) of p-toluene sulfonyl
chloride was added with stirring. The mixture was poured into 150
ml of ice water and the aqueous mixture was extracted with 150 ml
(3.times.50 ml) of ether. The combined ether extracts were washed
with 100 ml (2.times.50 ml) of ice cold 6 N hydrochloric acid and
100 ml of ice water. The resultant ether extract was dried over
anhydrous sodium sulfate-anhydrous potassium carbonate, filtered,
and the solvent was removed in vacuo to yield 2.87 g (96.9%) of the
title compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.1 (15H, multiplet), 2.48
(3H, singlet), 4.0 (2H, triplet, J=6 Hz), 7.5 ppm (4H, quartet, J=8
Hz).
B. Preparation of (Cyclobutylmethyl) tosylate
The title compound was prepared according to the procedure of
Example 10A by replacing 3-cyclohexylpropan-1-ol with (cyclobutyl)
methanol (prepared in Example 9B). The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9-2.1 (10H, multiplet), 2.4
(6H, singlet), 3.8 (4H, doublet, J=5 Hz), 7.4 ppm (8H,
multiplet).
C. Preparation of 5-Cyclododecylpentyl-1-tosylate
The title compound was prepared according to the procedure of
Example 10A by replacing 3-cyclohexylpropan-1-ol with
5-cyclododecylpentan-1-ol prepared in Example 9Ciii). The resultant
product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.0 (31H, multiplet), 2.5
(3H, singlet), 4.1 (2H, triplet, J=6 Hz), 7.55 ppm (4H, AB, J=8
Hz).
EXAMPLE 11
A. Preparation of Diethyl-2-(3-cyclohexylpropyl) malonate
Sodium metal (0.39 g, 0.0172 g/atom) was granulated by heating in
4.11 ml of dry xylene (distilled from sodium hydride) under
nitrogen with rapid stirring. The slurry was diluted with 16.44 ml
of dry xylene. Diethyl malonate (4.95 g, 4.70 ml, 0.031 mole) was
added and the mixture was heated to 150.degree. C. until the sodium
was consumed. 3-Cyclohexylpropyl-1-tosylate (2.69 g, 0.01 mole;
prepared by Example 11A) was dissolved in 8.22 ml of dry xylene and
added to the sodiodethyl malonate. This mixture was then heated to
150.degree. C. for 6 hr. The reaction mixture was cooled and 50 ml
of water was added. The phases were separated and the aqueous phase
was extracted with 70 ml (2.times.35 ml) of xylene. The xylene
extract was washed with 50 ml of 6 N hydrochloric acid and 50 ml of
water. The resulting extract was dried over anhydrous magnesium
sulfate, filtered, and the solvent was removed in vacuo. The
product was distilled at reduced pressure to yield 2.2 g (78.5%) of
the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.2 (23H, multiplet), 3.42
(1H, triplet, J=7 Hz), 4.3 ppm (4H, quarter, J=8 Hz).
B. Preparation of Diethyl (cyclobutylmethyl) malonate
The title compound was prepared according to Example 11A by
replacing 3-cyclohexylpropyl-1-tosylate with the (cyclobutylmethyl)
tosylate prepared in Example 10B. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.8 (20H, multiplet), 4.2 ppm
(4H, two overlapping quarters, J=8 Hz).
C. Preparation of Diethyl (5-cyclododecylpentyl) malonate
The title compound was prepared according to Example 11A by
replacing 3-cyclohexylpropyl)-1-tosylate with the
5-cyclododecylpentyl-1-tosylate prepared in Example 10C. The
resultant product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.0 (39H, multiplet), 3.3
(1H, triplet, J=8 Hz), 4.2 ppm (4H, quartet, J=6 Hz).
EXAMPLE 12
A. Preparation of 2-(3-Cyclohexylpropyl)-propane-1,3-diol
The title compound was prepared according to the procedure of
Example 1A by replacing diethyl ethylmalonate with
diethyl-2-(3-cyclohexylpropyl) malonate (prepared in Example 11A).
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3 : .delta.0.6-2.0 (18H, multiplet), and 3.1
to 4.3 ppm (6H, multiplet).
B. Preparation of 2-(Cyclobutylmethyl)-propane-1,3-diol
The title compound was prepared according to the procedure of
Example 12A by replacing diethyl-2-(3-cyclohexlpropyl) malonate
with diethyl-(cyclobutylmethyl) malonate (prepared in Example 11B).
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-2.8 (10H, multiplet), 3.1
(2H, broad singlet), and 3.8 ppm (4H, multiplet).
C. Preparation of 2-(5-Cyclododecylpentyl)-propane-1,3-diol
The title compound was prepared in 84.7% yield according to the
procedure of Example 12A by replacing
diethyl-2-(3-cyclohexylpropyl) malonate with the
diethyl-5-(cyclododecylpentyl) malonate prepared in Example
11C.
D. Preparation of
2-(3-Cyclohexylpropyl)-2-ethylpropane-1,3-diol
i. Diethyl-2-ethyl-2-(3-cyclohexylpropyl)-malonate
Sodium metal (3.16 g, 0.137 g/atom) was dispersed by heating with
rapid stirring in 80 ml of dry xylene at 110.degree. to 120.degree.
C. The mixture was cooled and the xylene was removed with a filter
stick. Dry toluene (300 ml distilled from calcium hydride) was
added thereto and followed by the addition of 28.17 g (0.149 mole)
of diethyl ethylmalonate. This mixture was slowly heated to
150.degree. C. 3-Cyclohexylpropyl-1-tosylate (28.3 g, 1.1956 mole;
prepared by Example 10A) was dissolved in 80 ml of dry toluene.
This solution was then added to the sodiodiethylethylmalonate above
and the mixture was stirred at 150.degree. C. for 10 hr. The
mixture was cooled and poured into 500 ml of water. The phases were
separated and the aqueous phase was extracted with 500 ml
(2.times.250 ml) of ether. The ether extract was washed with 250 ml
of saturated sodium chloride solution, dried over a anhydrous
magnesium sulfate and filtered. The solvents were removed in vacuo.
The product was distilled at reduced pressure to yield 19.4 g of
the title compound having the following physical
characteristics:
Analysis--NMR(CDl.sub.3): .delta.0.6-2.0 (28H, multiplet), 4.1 ppm
(4H, quartet, J=8 Hz).
ii. 2-(3-Cyclohexylpropyl)-2-ethyl-propane-1,3-diol
The title compound was prepared according to the procedure of
Example 12A by replacing diethyl-2-(3-cyclohexylpropyl) malonate
with the diethyl-2-ethyl-2-(3-cyclohexylpropyl) malonate prepared
in Example 11Di. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-1.9 (22H, multiplet), 3.1
(2H, broad multiplet), 3.5 ppm (2H, multiplet).
EXAMPLE 13
A. Preparation of 2-(3-Cyclohexylpropyl)-propane-1,3-ditosylate
The title compound was prepared according to the procedure of
Example 1B by replacing 2-ethylpropane-1,3-diol with
2-(3-cyclohexylpropyl)-propane-1,3-diol (prepared in Example 12A).
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.1 (18H, multiplet), 2.5
(6H, singlet), 3.95 (4H, doublet, J=5 Hz), and 7.55 ppm (8H, AB,
J=8 Hz).
B. Preparation of 2-(Cyclobutylmethyl)-propane-1,3-ditosylate
The title compound was prepared according to the procedure of
Example 13A by replacing 2-(3-cyclohexylpropyl)-propane-1,3-diol
with 2-(cyclobutylmethyl)-propane-1,3-diol prepared in Example 12B.
The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.4-2.3 (7H, multiplet), 2.55
(3H, singlet), 40.5 (1H, doublet, J=6 Hz), 7.55 ppm (4H, AB, J=8
Hz).
C. Preparation of
2-(5-Cyclododecylpentyl)-propane-1,3-ditosylate
The title compound was prepared according to the procedure of
Example 13A by replacing 2-(3-cyclohexylpropyl)-propane-1,3-diol
with 2-(5-cyclododecylpentyl)-propane-1,3-diol (prepared in Example
12C). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8-2.2 (34H, multiplet), 2.48
(6H, singlet), 4.05 (4H, multiplet), 7.55 ppm (8H, AB, J=8 Hz).
D. Preparation of
2-(3-Cyclohexylpropyl)-2-ethylpropane-1,3-ditosylate
The title compound was prepared according to the procedure
described in Example 13A by replacing
2-(3-cyclohexylpropyl)-propane-1,3-diol with
2-(3-cyclohexylpropyl)-2-ethylpropane-1,3-diol (prepared in Example
12D). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-1.8 (22H, multiplet), 2.47
(6H, singlet), 3.85 (4H, singlet), 7.7 ppm (8H, AB, J=10 Hz).
EXAMPLE 14
A. Preparation of
3-(3-Cyclohexylpropyl)-1,1-dicarbethoxycyclobutane
The title compound was prepared according to the procedure of
Example 1C by replacing 2-ethylpropane-1,3-ditosylate with
2-(3-cyclohexylpropyl)-propane-1,3-ditosylate (prepared in Example
13A). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.8 (26H, multiplet), and 4.4
ppm (4H, quartet, J=5 Hz); bp 115.degree. C./0.05 mm.
B. Preparation of
3-(Cyclobutylmethyl)-1,1-dicarbethoxycyclobutane
The title compound was prepared according to Example 14A by
replacing 2-(3-cyclohexylpropyl)-propane-1,3-ditosylate with
2-(cyclobutylmethyl)-propane-1,3-ditosylate prepared in Example
13B. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8-2.9 (20H, multiplet).
C. Preparation of
3-(5-Cyclododecylpentyl)-1,1-dicarbethoxycyclobutane
The title compound was prepared according to Example 14A by
replacing 2-(3-cyclohexylpropyl)-propane-1,3-ditosylate with
2-(5-cyclododecylpentyl)-propane-1,3-ditosylate prepared in Example
13C. The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (44H, multiplet), 4.2 ppm
(4H, A, J=6 Hz).
D. Preparation of
3-Ethyl-3-(3-cyclohexylpropyl)-1,1-dicarbethoxycyclobutane
The title compound was prepared according to the procedure of
Example 14A by replacing
2-(3-cyclohexylpropyl)-propane-1,3-ditosylate with
2-ethyl-2-(3-cyclohexylpropyl)-propane-1,3-ditosylate prepared in
Example 13D. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.0 (26H, multiplet), 2.35
(4H, singlet), 4.25 ppm (4H, quartet, J=9 Hz); bp
150.degree.-155.degree. C. C/0.2 mm.
EXAMPLE 15
A. Preparation of
3-(3-Cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic acid
The title compound was prepared according to the procedure of
Example 1D by replacing 3-ethyl-1,1-dicarbethoxycyclobutane with
3-(3-cyclohexylpropyl)-1,1-dicarbethoxycyclobutane (prepared in
Example 14A). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.8 (22H, multiplet) and 7.1
ppm (2H, singlet).
B. Preparation of 3-(Cyclobutylmethyl)-cyclobutane-1,1-dicarboxylic
acid
The title compound was prepared according to the procedure of
Example 15A by replacing
3-(3-cyclohexylpropyl)-1,1-dicarbethoxycyclobutane with
3-(cyclobutylmethyl)-1,1-dicarboethoxycyclobutane (prepared in
Example 14B). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-3.0 (14H, multiplet) and 8.95
ppm (2H, broad singlet).
C. Preparation of
3-(5-Cyclododecylpentyl)-cyclobutane-1,1-dicarboxylic acid
The title compound was prepared according to Example 15A by
replacing 3-(3-cyclohexylpropyl)-1,1-dicarboethoxycyclobutane with
3-(5-cyclododecylpentyl)-1,1-dicarboethoxycyclobutane (prepared in
Example 14C). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.8 (38H, multiplet), 8.0 ppm
(2H, broad singlet).
D. Preparation of
3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic
acid
The title compound was prepared according to Example 15A by
replacing 3-(3-cyclohexylpropyl)-1,1-dicarboethoxycyclobutane with
3-ethyl-3-(3-cyclohexylpropyl)-1,1-dicarboethoxycyclobutane
(prepared in Example 14D). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.65-0.9 (3H, triplet, J=8 Hz),
0.8-2.0 (22H, multiplet), 2.45 (4H, singlet), 8.25 ppm (2H, broad
singlet).
EXAMPLE 16
A. Preparation of 3-(3-Cyclohexylpropyl)-cyclobutanecarboxylic
acid
The title compound was prepared according to the procedure of
Example 1E by replacing 3-ethylcyclobutane-1,1-dicarboxylic acid
with 3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic acid
(prepared in Example 15A). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-3.3 (23H, multiplet) and 11.3
ppm (1H, singlet).
B. Preparation of 3-(Cyclobutylmethyl)-cyclobutanecarboxylic
acid
The title compound was prepared according to the procedure of
Example 16A by replacing
3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic acid with
3-(cyclobutylmethyl)-cyclobutane-1,1-dicarboxylic acid prepared in
Example 15B. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.8 (14H, multiplet), 1.3
(1H, multiplet), 12.5 ppm (1H, broad singlet).
C. Preparation of 3-(5-cyclododecylpentyl)-cyclobutanecarboxylic
acid
The title compound was prepared according to the procedure of
Example 16A by replacing
3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic acid with
3-(5-cyclododecylpentyl)-cyclobutane-1,1-dicarboxylic acid
(prepared in Example 15C). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.5 (39H, multiplet), 10.5
ppm (1H, broad singlet).
D. Preparation of
3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid
The title compound was prepared according to Example 16A by
replacing 3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic acid
with 3-ethyl-3-(3-cyclohexylpropyl)-cyclobutane-1,1-dicarboxylic
acid (prepared in Example 15D). The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.6 (27H, multiplet), 11.3
ppm (1H, broad singlet).
EXAMPLE 17
A. Preparation of 3-(3-Cyclohexylpropyl)-cyclobutanecarboxylic acid
chloride
The title compound was prepared according to the procedure of
Example 1F by replacing 3-ethylcyclobutanecarboxylic acid with
3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid (prepared in
Example 16A). The title compound had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-3.0 (22H, multiplet) and 3.5
ppm (1H, multiplet).
B. Preparation of 3-(Cyclobutylmethyl)-cyclobutanecarboxylic acid
chloride
The title compound was prepared according to Example 17A by
replacing 3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid with
3-(cyclobutylmethyl)-cyclobutanecarboxylic acid (prepared in
Example 16B). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.9 (14H, multiplet) and 3.45
ppm (1H, multiplet).
C. Preparation of 3-(5-Cyclododecylpentyl)-cyclobutanecarboxylic
acid chloride
The title compound was prepared according to Example 17A by
replacing 3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid with
3-(5-cyclododecylpentyl)-cyclobutanecarboxylic acid (prepared in
Example 16C). The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-3.0 ppm (39H, multiplet).
D. Preparation of
3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid
chloride
The title compound was prepared according to Example 17A by
replacing 3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid with
3-ethyl-3-(3-cyclohexylpropyl) cyclobutanecarboxylic acid prepared
in Example 16D. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.2 (26H, multiplet) and 3.3
ppm (1H, multiplet).
EXAMPLE 18
A. Preparation of
3-(3-Cyclohexylpropyl)-cyclobutyl-trans-.beta.-chlorovinyl
ketone
The title compound was prepared according to the procedure of
Example 1G by replacing 3-ethylcyclobutanecarboxylic acid chloride
with 3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid chloride
(prepared in Example 17A). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-2.6 (22H, multiplet), 3.2
(1H, multiplet), 6.4 (1H, doublet, J=12 Hz), 7.2 ppm (1H, doublet,
J=12 Hz).
B. Preparation of
3-(Cyclobutylmethyl)-cyclobutyl-trans-.beta.-chlorovinyl ketone
The title compound was prepared according to the procedure of
Example 19A by replacing
3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid chloride with
3-(cyclobutylmethyl)-cyclobutanecarboxylic acid chloride prepared
in Example 17B. The resultant product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.75 (14H, multiplet), 3.25
(1H, multiplet), 6.48 (1H, doublet, J=13 Hz), 7.3 ppm (1H, doublet,
J=13 Hz).
C. Preparation of
3-(5-Cyclododecylpentyl)-cyclobutyl-trans-.beta.-chlorovinyl
ketone
The title compound was prepared according to the procedure of
Example 18A by replacing
3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid chloride with
3-(5-cyclododecylpentyl)-cyclobutanecarboxylic acid chloride
prepared in Example 17C. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.5-2.7 (40H, multiplet), 6.3
(1H, doublet, J=13 Hz), 7.2 ppm (1H, doublet, J=13 Hz).
D. Preparation of
[3-Ethyl-3-(3-cyclohexyl-propyl)-cyclobutyl]-trans-.beta.-chlorovinyl-keto
ne
The title compound was prepared according to the procedure of
Example 18A by replacing
3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid chloride with
3-ethyl-3-(3-cyclohexylpropyl)-cyclobutanecarboxylic acid chloride
prepared in Example 17D. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.4 (26H, multiplet), 3.3 ppm
(1H, multiplet), 6.55 (1H, doublet, J=14 Hz), 7.4 ppm (1H, doublet,
J=14 Hz).
EXAMPLE 19
A. Preparation of
3-(3-Cyclohexylpropyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
The title compound was prepared according to the procedure of
Example 1H by replacing 3-ethylcyclobutyl-trans-.beta.-chlorovinyl
ketone with
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-chlorovinyl ketone
(prepared in Example 18A). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (22H, multiplet), 3.3
(1H, multiplet), 7.15 (1H, doublet, J=15 Hz) and 7.75 ppm (1H,
doublet, J=15 Hz).
B. Preparation of
3-(Cyclobutylmethyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
The title compound was prepared according to the procedure of
Example 19A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-chlorovinyl ketone
with 3-(cyclobutylmethyl)-cyclobutyl-trans-.beta.-chlorovinyl
ketone prepared in Example 18B. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.5 (14H, multiplet), 3.2
(1H, multiplet), 7.0 (1H, doublet, J=16 Hz), 7.7 ppm (1H, doublet,
J=16 Hz).
C. Preparation of
3-(5-Cyclododecylpentyl)-cyclobutyl-trans-.beta.-iodovinyl
ketone
The title compound was prepared according to the procedure of
Example 19A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-chlorovinyl ketone
with 3-(5-cyclododecylpentyl)-cyclobutyl-trans-.beta.-chlorovinyl
ketone prepared in Example 18C. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (38H, multiplet), 3.4
(1H, multiplet), 7.2 (1H, doublet, J=13 Hz), 7.7 ppm (1H, doublet,
J=13 Hz).
D. Preparation of
[3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutyl]-trans-.beta.-iodovinyl
ketone
The title compound was prepared according to the procedure of
Example 19A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-chlorovinyl ketone
with
[3-ethyl-3-(3-cyclohexylpropyl)-cyclobutyl]-trans-.beta.-chlorovinyl
ketone prepared in Example 18D. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (27H, multiplet), 7.2
(1H, doublet, J=17 Hz), 7.8 ppm (1H, doublet, J=17 Hz).
EXAMPLE 20
A. Preparation of
1-[3-(Cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
The title compound was prepared according to the procedure of
Example 1I by replacing 3-ethylcyclobutyl-trans-.beta.-iodovinyl
ketone with
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
(prepared in Example 19A). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (22H, multiplet), 3.8-4.3
(2H, multiplet) and 6.1-6.6 ppm (2H, multiplet).
B. Preparation of
1-[3-(Cyclobutylmethyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
The title compound was prepared according to the procedure of
Example 20A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
with 3-(cyclobutylmethyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
prepared in Example 19B. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.9 (15H, multiplet), 4.25
(1H, multiplet), 6.6 ppm (2H, multiplet).
C. Preparation of
1-[3-(5-Cyclododecylpentyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
The title compound was prepared according to the procedure of
Example 20A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
with 1-[3-(5-cyclododecylpentyl)-cyclobutyl]-trans-.beta.-iodovinyl
ketone prepared in Example 19D. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.2 (39H, multiplet), 2.5
(1H, broad singlet), 4.0 (1H, multiplet), 6.1-6.6 ppm (2H,
multiplet).
D. Preparation of
1-[3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
The title compound was prepared according to the procedure of
Example 20A by replacing
3-(3-cyclohexylpropyl)-cyclobutyl-trans-.beta.-iodovinyl ketone
with
[3-ethyl-3-(cyclohexylpropyl)-cyclobutyl]-trans-.beta.-iodovinyl
ketone prepared in Example 19D. The resultant product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (29H, multiplet), 4.0
(1H, multiplet).
EXAMPLE 21
A. Preparation of
1-[3-(3-Cyclohexylpropyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-iodoprop-
2-ene
The title compound was prepared according to the procedure of
Example 1J by replacing
1-(3-ethylcyclobutyl)-trans-3-iodoprop-2-en-1-ol with
1-[3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
(prepared in Example 20A). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.6-2.5 (29H, multiplet), 3.65
(3H, multiplet), 4.75 (1H, quartet, J=6Hz) and 6.0-6.7 ppm (2H,
multiplet).
B. Preparation of
1-[3-(Cyclobutylmethyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-iodoprop-2-
ene
The title compound was prepared according to Example 21A by
replacing
1-[3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
with 1-[3-(cyclobutylmethyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
(prepared in Example 20B). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.7 (21H, multiplet), 3.6
(3H, multiplet), 4.7 (1H, quartet, J=6 Hz) 6.1-6.7 ppm (2H,
multiplet).
C. Preparation of
1-[3-(5-Cyclododecylpentyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-iodopro
p-2-ene
The title compound was prepared according to Example 21A by
replacing
1-[3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
with
1-[3-(5-cyclododecylpentyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
prepared in Example 20C. The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.7-2.3 (45H, multiplet), 3.5
(3H, multiplet), 4.65 (1H, multiplet), 6.0-6.5 ppm (2H,
multiplet).
D. Preparation of
1-[3-Ethyl-3-(3-cyclohexylpropyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-i
odoprop-2-ene
The title compound was prepared according to Example 21A by
replacing
1-[3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
with
1-[3-ethyl-3-(3-cyclohexylpropyl)-cyclobutyl]-trans-3-iodoprop-2-en-1-ol
(prepared in Example 20D). The resultant product had the following
physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8-2.5 (33H, multiplet), 3.3-4.1
(3H, multiplet), 4.75 (1H, quartet, J=6 Hz), 6.15-6.8 ppm (2H,
multiplet).
EXAMPLE 22
This example illustrates the preparation of
1-(tetrahydropyran-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent
-1-enyl] heptane and
1-(tetrahydropyran-2-yloxy)-6-[3RS-(tetrahydropyran-2-yloxy)-5-oxocyclopen
t-1-enyl] hexane.
A-1 Preparation of Ethyl 9-oxodecanoate ethylene ketal
A solution containing 77.5 g (362 mmol) of ethyl 9-oxodecanoate
(prepared described in J. Amer. Chem. Soc., 68: 832 [1946]), 22.4 g
(362 mmol) of ethylene glycol and 438 mg of p-toluenesulfonic acid
in 150 ml of dry benzene was refluxed for 4.5 hr with a Dean Stark
trap. A 7.0 ml portion of water (theoretical=6.5 g) collected in
the trap. The solution was cooled to room temperature and then was
washed with saturated aqueous sodium bicarbonate. The aqueous phase
was back-extracted twice with ether. The combined ether extracts
were dried over Na.sub.2 SO.sub.4 and evaporated in vacuo and
distilled in vacuo to give a 83.5% yield of the title compound. The
product had the following physical characteristics:
Analysis--bp 101.degree.-110.degree. C. (0.2 mm); NMR(CDCl.sub.3)
.delta.1.27 (3H, singlet), 1.23 (3H, triplet, J=7 Hz), 1.0 to 2.5
(14H, multiplet), 3.92 (4H, singlet) and 4.13 ppm (2H, quartet, J=7
Hz).
A-2 Preparation of 9-Oxodecan-1-ol
A solution of 95.4 g (370 mmol) of ethyl 9-oxodecanoate ethylene
ketal (prepared in Example 22A-1) in 120 ml of ether was added
dropwise to a stirred mixture of 10.5 g (277 mmol) of lithium
aluminum hydride and 500 ml of ether under argon. The mixture was
stirred for 18 hr and then quenched by the dropwise addition of 18
ml of ethyl acetate. To this mixture there was then sequentially
added in dropwise fashion, with stirring, 10.5 ml of water, 10.5 ml
of 15% aqueous sodium hydroxide and 31.1 ml of water. The mixture
was stirred for about 2 to 3 hr and the mixture was then filtered.
The filter pad was rinsed several times with ether. The combined
filtrates were evaporated in vacuo. The residue was dissolved in a
mixture of 250 ml of 10% hydrochloric acid and 120 ml of methanol
and left to stand at room temperature for about 4 hr. The solution
was evaporated in vacuo. This residue was dissolved in ether and
the resulting solution was washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate and evaporated in
vacuo to yield 74.3 g of a yellow oil. The product had the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0-2.0(12H, multiplet), 2.12
(3H, singlet), 3.43 (2H, broad triplet, J=7 Hz), 2.9 (1H, broad
singlet), 1.15 (3H, doublet, J=6 Hz) and 3.6 ppm (2H, broad
triplet, J=Hz).
B-1 Preparation of Oct-7-en-1-ol
A mixture containing 1.7 liter of anhydrous tetrahydrofuran
(distilled from sodium/benzophenone ketyl) and 600 g (5.4 mol) of
distilled 1,7-octadiene (Aldrich Chemical Co. Inc.) was prepared
under nitrogen. Borane in tetrahydrofuran (1 M, 600 ml, 0.60 mol)
was added dropwise to the mixture over a 1.0 hr period while the
mixture was maintained at 25.degree. C. The resultant solution was
stirred for 1 hr at room temperature and then 25 ml of water was
added thereto followed by 300 ml of 3 M sodium hydroxide. These
additions were followed by 300 ml of 30% aqueous hydrogen peroxide
while maintaining the mixture at 30.degree. to 40.degree. C. The
mixture was stirred for 15 min and the phases which formed were
separated. The aqueous phase was extracted 3 times with an equal
volume of pentane. The combined pentane extracts were washed with
200 ml of 10% aqueous sodium bisulfite, then with saturated aqueous
sodium chloride and then dried over magnesium sulfate. The mixture
was filtered and the filtrate was evaporated and distilled to yield
the title compound (bp 62.degree.-64.degree. C., 20 mm) as a
colorless oil having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.35 (8H, multiplet), 1.97 (2H,
broad triplet), 2.90 (1H, singlet), 3.57 (2H, broad triplet, J=7
Hz), 4.75.2 (2H, multiplet), 5.56.2 ppm (1H, multiplet);
IR(CHCl.sub.3).nu.: 3600, 3250, 3060, 2930, 2850, 1620, 1040, and
900 cm.sup.-1.
B-2 Preparation of Oct-7-enoic acid
To a stirred solution of 152 g of oct-7-en-1-ol (prepared in
Example 22 B-1) in 3.4 liters of acetone there was added 1.4 M of
Jones Reagent (986 ml) while the mixture was maintained at less
than 10.degree. C. The mixture was stirred for 10 min and was
quenched with 100 ml of isopropanol. The acetone volume was reduced
in vacuo and the residue was diluted with water and extracted three
times with equal volumes of ethyl acetate. The combined ethyl
acetate extracts were washed two times with water, then with
saturated aqueous sodium chloride, dried over magnesium sulfate and
evaporated in vacuo to yield 164 g of the title compound having the
following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-1.9 (6H, multiplet), 2.1 (2H,
triplet, J=7 Hz), 2.5 (2H, triplet, J=7 Hz), 5.1 (2H, three
doublets, J=14,10,2 Hz), 6.0 (1H, two doublets, one quartet,
J=14,10,7H); IR(CHCl.sub.3).nu.: 3600-3000 (broad), 2925, 1705,
1640 and 905 cm.sup.-1.
B-3 Preparation of Non-8-en-2-one
To a stirred mixture of 11.0 g lithium hydride in 800 ml of
anhydrous ether, there was added dropwise 164 g of oct-7-enoic acid
(prepared in Example 22 B-2) in 800 ml of anhydrous ether and the
mixture was cooled to 0.degree. C. and 650 ml of 2 M methyllithium
in ether was added dropwise and then allowed to warm to room
temperature and stir for 4.5 hr. This mixture was quenched by
pouring the slurry into rapidly stirred 10% aqueous hydrochloric
acid (1.2 liter) and wet ice. The resulting mixture was extracted
with ether (3.times.700 ml). The continued ether extracts were
washed with 10% aqueous sodium hydroxide and then with saturated
aqueous sodium chloride and dried over anhydrous magnesium sulfate.
The solvent was removed in vacuo to yield 118.9 g of the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-1.9 (6H, multiplet), 2.1 (2H,
triplet, J=7 Hz), 2.2 (3H, singlet), 2.5 (2H, triplet, J=7 Hz), 5.1
(2H, three doublets, J=14,10,2 Hz), 6.0 (1H, two doublets, one
quartet, J=14,10,7 Hz); IR(CHCl.sub.3).nu.: 2925, 1705, 1640, and
905 cm.sup.-1.
B-4 Preparation of Non-8-en-2-one ethylene ketal
A solution containing 119.0 g of non-8-en-2-one, (prepared in
Example 22 B-3), 1.2 g p-toluenesulfonic acid monohydrate, 63.1 g
of ethylene glycol and 420 ml anhydrous benzene was prepared and
refluxed for about 15 to 17 hr. Water which formed was collected in
a Dean-Stark trap. The solution was cooled to room temperature and
250 ml of 5% aqueous sodium bicarbonate solution was added thereto.
The benzene layer was separated and dried over anhydrous magnesium
sulfate and evaporated in vacuo. The residue was distilled to yield
116.8 g of title compound having the following physical
characteristics:
Analysis--bp 80.degree.-85.degree. C. (5 torr); NMR(CDCl.sub.3):
.delta.1.3-2.3 (13H, multiplet), 4.0 (4H, singlet), 5.1 (2H, three
doublets, J=14,10,2 Hz), 6.0 (1H, two doublets, one quartet,
J=14,10,7 Hz); IR(CHCl.sub.3).nu.: 2925, 1640, 1380, 1060 and 910
cm.sup.-1.
B-5 Preparation of 8-oxonononan-1-ol-ethylene ketal
A mixture of 320 ml of anhydrous tetrahydrofuran and 58.4 g (0.32
mol) of non-8-en-2-one ethylene ketal prepared in Example 22 B-4)
under nitrogen was prepared and 176 ml of 1 M (0.176 mol) of borane
in tetrahydrofuran was added thereto over about a 1.0 hr period
while maintaining the mixture at about 25.degree. C. Water (7.5 ml)
followed by 88 ml of 3 M sodium hydroxide and then 88 ml of 30%
aqueous hydrogen peroxide were slowly added while maintaining the
temperature at about 30.degree. to 40.degree. C. The resulting
mixture was stirred for about 15 min and the phases which formed
were separated. The aqueous layer was extracted three times with an
equal volume of pentane. The combined pentane extracts were washed
with 10% aqueous sodium bisulfite, then with saturated aqueous
sodium chloride and then dried over anhydrous magnesium sulfate.
The mixture was filtered, evaporated and the residue distilled to
yield the title compound having the following physical
characteristics:
Analysis--bp 106.degree.-110.degree. C. (5 mm); NMR(CDCl.sub.3):
.delta.1.2-2.1 (16H, multiplet), 3.7 (2H, broad triplet, J=6 Hz),
and 4.0 ppm (4H, singlet); IR(CHCl.sub.3).nu.: 3600, 3450 (broad),
2920, 1460, 1375 and 940 cm.sup.-1.
B-6 Preparation of 8-oxononan-1-ol
A solution containing 56.6 g of 8-oxononan-1-ol ethylene ketol
(prepared in Example 22 B-5) in 210 ml acetone and 50 mg
p-toluenesulfonic acid monohydrate was stirred at room temperature
for about 15 to 17 hr. The acetone was removed in vacuo to yield
the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-2.0 (11H, multiplet), 2.2
(3H, singlet), 2.5 (2H, triplet, J=7 Hz), 3.7 (2H, broad triplet,
J=6 Hz); IR(CDCl.sub.3).nu.: 3600 (sharp), 3450 (broad) 2925, 1710,
1260 and 1045 cm.sup.-1.
C-1 Preparation of 7-(2,3,5-trioxocyclopentyl)-heptan-1-ol
A 4.63 g (201 mmol) portion of sodium was dissolved in 100 ml of
dry ethanol under nitrogen. This solution was cooled to 0.degree.
C. and stirred as 17.2 g (100 mmol) of 9-oxo-1-decanol (prepared in
Example 22 A-2) in 30 ml of diethyloxolate was added dropwise over
25 min. After stirring for 15 hr at room temperature under
nitrogen, the resulting solution was refluxed for 1 hr. The
solution was then poured into 100 ml of 10% hydrochloric acid and
evaporated in vacuo to yield an oil. This oil was refluxed for 5 hr
with 600 ml of 2 N hydrochloric acid. The aqueous phase was
separated and the remaining oil was extracted with 100 ml of hot 2
N hydrochloric acid. The combined acidic extracts were cooled for
about 15 to 17 at 0.degree. C. A crystalline product which formed
was collected by filtration, washed with cold water and dried in
vacuo over phosphorus pentoxide to yield the title compound having
the following physical characteristics:
Analysis--mp 121.degree.-124.degree. C.; NMR(acetone-d.sub.6)
.delta.: 1.1-1.8 (12H, multiplet), 2.38 (2H, broad triplet, J=6.5
Hz), 2.86 (2H, singlet) and 3.53 ppm (2H, broad triplet, J=61 Hz);
IR(Nujol).nu.: 1060, 1170, 1260, 1380, 1435, 1650, 1680, 1730,
2950, 3200 cm.sup.-1 ; UV max (CH.sub.3 OH) 232 .mu.m
(.epsilon.11,700) and 325 .mu.m (.epsilon.11,400); MS(70 eV) m/e
227, 226 (parent), 208, 198, 180, 153, 152, 151, 140, 139, 138,
137, 126 (base), 55, 43 and 41.
C-2 Preparation of 6-(2,3,5-trioxocyclopentyl)-hexan-1-ol
The title compound was prepared using the procedure of Example 9
C-2 by replacing 9-oxodecan-1-ol with 8-oxononan-1-ol (prepared in
Example 22 B-6). The product had the following physical
characteristics:
Analysis--NMR(acetone-d.sub.6) .delta.:1.1-1.8 (8H, multiplet) 2.4
(2H, broad triplet, J=7 Hz), 3.0 (2H, singlet), 3.6 (2H, broad
triplet J=6 Hz), 5.8-6.8(2H, broad, D.sub.2 O exchangeable);
IR(KBr).nu.: 3450(broad), 2925, 1740, 1675, 1650, 1440, 1280, 1240,
1060 cm.sup.-1 ; UV(methanol): 324 .mu.m (11,600), 232 .mu.m
(11,000); MS(70 eV): 212 (parent) 194 (p-H.sub.2 O), 184, 166, 126
(base peak).
D-1 Preparation of
7-(3R-Hydroxy-2,5-dioxocyclopentyl)-heptan-1-ol
A soybean-glucose medium containing 50 g soybean meal; 20 g
glucose; 50 g yeast extract; 50 g K.sub.2 HPO.sub.4 ; 50 g NaCl;
distilled water to 10 l; and pH adjusted to 6.5 with HCl was
prepared. The soybean-glucose medium was innoculated with a culture
of Dipodascus uninucleatus and 17 g of 7-(2,3,5-trioxocyclopentyl)
heptan-1-ol (prepared in Example 9 C-1) was added thereto and
incubated at 25.degree. C. for 24 hr. The resultant beer was
extracted several times with ethyl acetate. The contained ethyl
acetate extracts were dried over Na.sub.2 SO.sub.4 and evaporated
in vacuo to yield the title compound having the following physical
characteristics:
Analysis--mp 101.degree.-104.degree. C.; NMR(acetone-d.sub.6)
.delta.: 1.1-1.8 (10H, broad), 1.8-2.4 (3H, multiplet), 2.75 (1H, d
of d, J=17, 6.5 Hz), 3.53 (2H, broad triplet, J=6 Hz), 4.6 (1H, d
of d, J=6,2 Hz) and 5.5 ppm (3H, broad singlet); IR (Nujol mull):
1090, 1380, 1465, 1560, 2940 and 3100-3500 cm.sup.-1 (broad);
CD[d].sub.281 -95, 400.degree. (c 0.85, CHCl.sub.3); MS(70 eV)m/e:
228 (p), 210, (p-H.sub.2 O), 192 (p-2H.sub.2 O), 182, 169, 155,
128, 110 and other below 100.
E-1 Preparation of 7-(3R-Hydroxy-5-oxocyclopent-1-enyl)
heptan-1-ol
To a stirred solution of 228.2 mg (1.0 mmol) of
7-(3R-hydroxy-2,5-dioxocyclopentyl)-heptan-1-ol (prepared in
Example 9 D-1) in 3.0 ml of dry tetrahydrofuran at -10.degree. C.
under argon, there was added 0.3 ml (2.15 mol) of dry triethylamine
and then 218.3 mg (1.0 mol) of 2-mesitylenesulfonyl chloride
(Aldrich Chemical Co., Fieser 1,661) in 2 ml of dry
tetrahydrofuran. The resulting mixture was stirred at -10.degree.
to 0.degree. C. for 40 min and then at room temperature for 1.5 hr.
The mixture was diluted with ether, washed with 10% hydrochloric
acid, then saturated aqueous sodium chloride and finally saturated
aqueous sodium bicarbonate. The extract was dried over anhydrous
magnesium sulfate and evaporated in vacuo to yield 0.3828 g of
7-[3R-hydroxy-5-oxo-2-(mesitylenesulfonyloxy)-cyclopent-1-enyl)]-heptan-1-
ol. This mesitylenesulfonate in 6 ml of dry tetrahydrofuran was
then added dropwise to a stirred solution of 1.15 g (4.0 mol) of
Red-Al.RTM. (Aldrich Chemical Co., 70% solution of sodium
bis-(2-methoxyethoxy)-aluminum hydride in benzene; Fieser
2,382;3,260) in 3 ml of dry tetrahydrofuran under argon at
-78.degree. C. The resultant solution was stirred for 1.5 hr and
then quenched by addition of 1.5 ml of acetic acid. The mixture was
diluted with ether and shaken with several ml of 10% hydrochloric
acid until all solids had dissolved. The organic phase was
separated and washed with saturated aqueous sodium chloride. The
combined wash solution was back-extracted twice with ether. The
combined ether extracts were washed with aqueous sodium
bicarbonate, dried over anhydrous magnesium sulfate, and evaporated
in vacuo to yield
7-[4R,5RS-dihydroxy-2-(mesitylenesulfonyloxy)-cyclopent-1-enyl)]-heptan-1-
ol as a clear oil. This oil was dissolved in 5 ml of chloroform and
stirred under argon with 85 mg of sodium oxolate and 36 mg of
oxalic acid (hydrate). After 2 hr, the mixture was washed with
saturated aqueous sodium bicarbonate. The wash solution was
back-extracted twice with chloroform. The combined chloroform
extracts were dried over Na.sub.2 SO.sub.4 and evaporated in vacuo
to yield 0.2114 g of the crude title compound which was purified by
preparative thin layer chromatography. The pure title compound had
the following physical characteristics:
Analysis--mp 62.degree.-64.degree. C.; NMR(CDCl.sub.3):
.delta.0.8-1.9 (10H, broad multiplet), 2.2 (2H, broad multiplet),
2.26 (1H, d of d, J=2.5, 19 Hz), 2.82 (1H, d of d, J=6, 19 Hz), 3.6
(2H, broad triplet, J=6 Hz), 4.03 (2H, singlet), 4.9 (1H,
multiplet) and 7.2 ppm (1H, broad singlet); IR(CHCl.sub.3).nu.:
1030, 1710, 2860, 2930, 3005, 3200-3550 (broad) and 3600 cm.sup.-1
; UVmax(CH.sub.3 OH) 223 .mu.m (.epsilon.8,300); Mass Spectrum (70
eV)m/e 213, 212 (parent), 194, 168, 149, 135, 122, 95, 82, 81, 69,
67, 55, 43 (base) and 41. [.alpha.].sub.D.sup.25 +17.2.degree. (c
0.53, CH.sub.3 OH), +12.7 (c 1.09, CHCl.sub.3).
E-2. Preparation of 6-(3 RS-Hydroxy-5-oxocyclopent-1-enyl)
hexan-1-ol
The title compound was prepared using the procedure of Example 9
E-1 by replacing 7-(3R-hydroxy-2,5-dioxocyclopentyl) heptan-1-ol
with 6-(3RS-hydroxy-2,5-dioxocyclopentyl) hexan-1-ol (prepared in
Example 21 D-2). The product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-2.0 (8H, multiplet), 2.0-2.6
(2H, multiplet), 2.75 (1H, doublet, J=5.5 Hz), 3.1 (1H, doublet,
J=5.5 Hz), 3.4 (2H, broad singlet, D.sub.2 O exchangeable), 3.7
(2H, broad triplet, J=6 Hz), 5.05 (1H, multiplet), 7.35 (1H,
multiplet); IR(CHCl.sub.3).nu.: 3600 (sharp), 3550-3100 (broad),
2930, 1710, 1210, 1030, 945 cm.sup.-1 ; Mass Spectrum (70 eV): 198
(parent), 180 (p.+-.H.sub.2 O), 168, 154, 149, 95, 85 (base
peak).
F-1. Preparation of
1-(Tetrahydropyran-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent
-1-enyl] heptane
A mixture of 338 mg (1.59 mmol) of
7-(3R-hydroxy-5-oxocyclopent-1-enyl)-heptan-1-ol (prepared in
Example 9 E-1); 0.775 ml (8.5 mol) of freshly distilled
dihydropyran and 5 mg of toluenesulfonic acid in 5 ml of ether was
stirred at room temperature under nitrogen for about 3 hr. The
mixture was diluted with ether and washed with a small portion of
aqueous sodium bicarbonate. The ether solution was dried over
Na.sub.2 SO.sub.4 and evaporated in vacuo to yield the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.0 to 2.8 (26H, broad
multiplet), 3.2 to 4.2 (6H, multiplet), 4.5 to 5.1 (3H, multiplet)
and 7.2 ppm (H, broad singlet).
F-2. Preparation of
1-(Tetrahydropyran-2-yloxy)-6-[3RS-(tetrahydropyran-2-yloxy)-5-oxocyclopen
t-1-enyl] hexane.
The title compound was prepared according to the procedure of
Example 9 F-1 by replacing
7-(3R-hydroxy-5-oxocyclopent-1-enyl)heptan-1-al with
6-(3RS-hydroxy-5-oxocyclopent-1-enyl)hexan-1-ol (prepared in
Example 21 E-2). The product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-2.0 (20H, multiplet), 2.1-2.4
(2H, multiplet), 2.5-3.0 (2H, H.sub.A H.sub.B of ABX pattern),
3.4-4.3 (6H, multiplet) 4.7 (1H, multiplet), 5.0 (2H, multiplet),
7.4 (1H, multiplet); IR(CHCl.sub.3).nu.: 2930, 1710, 1640, 1340,
1120, 1075, 1020, 980, 900, 860 cm.sup.-1.
EXAMPLE 23
This example illustrates the preparation of:
A. 16,18-Methano-1,11.alpha.,15S-trihydroxyprost-13E-en-9-one
(TR-4570); and
B. 16,18-Methano-1,11.alpha.,15R-trihydroxyprost-13E-en-9-one
(TR-4569).
A solution of 2.54 g (7.5 mol) of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propane prepared
in Example 1-J in 15 ml of dry ether was stirred under argon with
dry ice-acetone bath cooling as 10.4 ml (15.0 mol) of a solution of
t-butyllithium in pentane (1.44 M) was added dropwise over 2 min
and stirred for 2 hr at -78.degree. C.
A second solution was prepared by stirring a dispersion of 1.96 g
(15 mol) of copper(I) pentyne in 25 ml of dry ether with 6.0 ml of
hexamethylphosphorus triamide under argon until the solution
becomes homogeneous. One half of the resulting solution was then
transferred via syringe to the above alkenyllithium solution as it
was stirred at -78.degree. C.
After 45 min, a third solution of 1.90 g (5.0 mol) of
1-(tetrahydropyran-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent
-1-enyl]heptane (prepared in Example 22-F-1) in 5 ml of ether was
added dropwise to the above alkenyl copper solution as it was
stirred at -78.degree. C. The resultant dispersion was stirred at
-78.degree. C. for 1.5 hr, then it was warmed over a 1 hr period to
-20.degree. C. and stirred at -20.degree. C. for 2 hr.
The resultant mixture was quenched by the addition of 200 ml of 2%
aqueous sulfuric acid. The resultant slurry was mixed thoroughly
and then filtered through Celite (diatomaceous earth). The phases
which formed in the filtrate were separated and the ether phase was
washed with saturated aqueous sodium chloride and then with
saturated aqueous sodium bicarbonate. The washed ether phase was
dried over anhydrous magnesium sulfate and evaporated in vacuo to
yield an oily residue. The oily residue was mixed with 45 ml of
(65:35 V/V) acetic acid-water and 5 ml of tetrahydrofuran and
stirred under argon for 45 hr at room temperature. The solvents
were removed by evaporation in vacuo to give 2.56 g of a yellow
residue. This residue was chromatographed on silicic acid-Celite
(diatomaceous earth) (85:15) using benzene to ethyl acetate
gradient elution to yield 324 mg of title compound TR-4570 above
and 327 mg of title compound TR-4569. An earlier cut of less polar
components (containing tetrahydropyranyl protected forms of TR-4570
and TR-4569) was separated and used as the starting material in
Example 28 below.
A. Title compound TR-4570 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, broad triplet, J=6.5
Hz): 1.0-2.7 (24H, multiplet), 3.2 (3H, broad singlet), 3.64 (2H,
broad triplet, J=5.5 Hz), 4.02 (2H, multiplet) and 5.75 ppm (2H,
multiplet); IR(film).nu.: 970, 1080, 1160, 1460, 1735, 2860, 2930
and 3100 to 3600 cm.sup.-1 (broad); Mass spectrum (70 eV)m/e: 334
(p-H.sub.2 O), 316 (p-2H.sub.2 O), 369 (p-(.sub.6 H.sub.11), 351
(p-H.sub.2 O-(.sub.6 H.sub.11), 234 (p-H.sub.2 O-HO-(.sub.6
H.sub.11); Optical Rotation: [.alpha.].sub.D -61.degree. (c 1.0,
CHCl.sub.3).
B. Title compound TR-4569 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, broad triplet, J=6.5
Hz), 1.0-2.7 (24H, multiplet), 3.4 to 4.2 (7H, multiplet) and 5.61
ppm (2H, multiplet); Optical Rotation [.alpha.].sub.D -41.5.degree.
C. (c 1.0, CHCl.sub.3).
EXAMPLE 24
This example illustrates the preparation of:
A.
16,18-Methano-16-methyl-1,11.alpha.,15S-trihydroxyprost-13E-en-9-one
(TR-4689); and
B.
16,18-Methano-16-methyl-1,11.alpha.,15R-trihydroxyprost-13E-en-9-onc
(TR-4688).
Repeating in a similar manner the procedure of Example 23, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethyl-cyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethyl-1-methylcyclobutyl) 1E-propene
(prepared in Example 7-A) yields title compound TR-4689 and title
compound TR-4688.
A. Title compound TR-4589 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, broad triplet, J=6.5
Hz) 1.07 and 1.13 (3H total, two singlets for methyl on isomers at
C-16), 1.0 to 3.0 (23H, multiplet), 2.72 (3H, broad singlet), 3.67
(2H, broad triplet, J=5.5 Hz), 3.9-4.3 (2H, multiplet) and 5.80 ppm
(2H, multiplet); IR(CHCl.sub.3).nu.: 970, 1070, 1380, 1465, 1740,
2860, 2940, 3200 to 3600 cm.sup.-1 (broad); Mass Spectrum (70
eV)m/e: 348 (p-H.sub.2 O), 330 (p-2H.sub.2 O), 276, 268 (p-C.sub.7
H.sub.14); Optical Rotation: [.alpha.].sub.D -64.3.degree. (c 0.96,
CHCl.sub.3).
B. Title compound TR4688 had the following physical
characteristics:
Analysis--NMR,IR and Mass Spectrum similar to title compound
TR-4689 above; Optical Rotation [.alpha.]-50.1.degree. (c 0.98,
CHCl.sub.3).
EXAMPLE 25
This example illustrates the preparation of:
A.
16,19-Cyclo-16-methyl-20-nor-1,11.alpha.,15S-trihydroxyprost-13E-en-9-one
(TR-4674); and
B.
16,19-Cyclo-16-methyl-20-nor-1,11.alpha.,15R-trihydroxyprost-13E-en-9-one
(TR-4673).
Repeating in a similar manner the procedure of Example 23, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(1-methylcyclobutyl)-1E-propene
(prepared in Example 7-B) yields title compound TR-4674 and title
compound TR-4673.
A title compound TR-4674 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.14 (3H, singlet), 1.0-3.0 (22H,
multiplet), 2.9 (3H, broad singlet), 3.67 (2H, broad triplet, J=5.5
Hz), 4.15 (2H, multiplet) and 5.82 ppm (2H, multiplet);
IR(CHCl.sub.3).nu.: 970, 1070, 1220, 1740, 2860, 2930 and 3200 to
3600 cm.sup.-1 (broad); Mass Spectrum (70 eV)m/e: 3.20 (p-H.sub.2
O), 302 (p-2H.sub.2 O-C.sub.5 H.sub.9); Optical Rotation:
[.alpha.].sub.D -61.7.degree. (c 1.0, CHCl.sub.3).
B. Title compound TR-4673 had the following physical
characteristics:
Analysis--NMR, IR, and Mass Spectrum similar to title compound
TR-4674 above; Optical Rotation: [.alpha.].sub.D -55.degree. (c
1.0, CHCl.sub.3).
EXAMPLE 26
This example illustrates the preparation of:
A. 16,16-Propano-1,11.alpha.,15S-trihydroxyprost-13E-en-9-one
(TR-4646); and
B. 16,16-Propano-1,11.alpha.,15R-trihydroxyprost-13E-en-9-one
(TR-4645).
Repeating in a similar manner the procedure of Example 23, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(1-butylcyclobutyl)-1E propene
(prepared in Example 7-C) yields title compound TR-4646 and title
compound TR-4645.
A title compound TR-4646 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, broad triplet, J=6.5
Hz), 1.0 to 2.8 (20H, multiplet), 3.68 (2H, broad triplet, J=5.5
Hz), 4.2 (2H, multiplet) and 5.83 ppm (2H, multiplet);
IR(CHCl.sub.3).nu.: 970, 1070, 1740, 2860, 2930, and 3200 to 3600
cm.sup.-1 (broad); Mass Spectrum (70 eV)m/e: 390 (p-H.sub.2 O), 297
(p-C.sub.8 H.sub.15); Optical Rotation: [.alpha.].sub.D
-52.9.degree. (c 1.09, CHCl.sub.3).
B. Title compound TR-4645 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to title compound
TR-4646 above; Optical Rotation: [.alpha.].sub.D -77.4.degree. (c
0.78, CHCl.sub.3).
EXAMPLE 27
This example illustrates tthe preparation of:
A.
(.+-.)16,18-Methano-1-nor-2,11.alpha.,15S-trihydroxyprost-13E-en-9-one
(TR-4676); and
B.
(.+-.)16,18-Methano-1-nor-2,11.alpha.,15R-trihydroxyprost-13E-en-9-one
(TR-4675).
Repeating in a similar manner the procedure of Example 23, but
respectively replacing
1-(tetrahydropyran-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent
-1-enyl]heptane with
1-(tetrahydropyran-2-yloxy)-6-[3RS-(tetrahydropyran-2-yloxy)-5-oxocyclopen
t-1-enyl] hexane (prepared in Example 22 F-2) to yield the title
compounds TR-4676 and TR-4675.
A Title compound TR-4676 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9 (3H, triplet, J=6 Hz),
1.1-2.8 (25H, multiplet), 3.65 (2H, triplet, J=6 Hz), 3.9-4.5 (2H,
multiplet), 5.75 (2H, multiplet); IR(CHCl.sub.3).nu.: 3600 (sharp),
3380 (broad), 2925, 1730, 1450, 1065, 965 cm.sup.-1 ; Mass Spectrum
(70 eV)m/e: no parent (338), 320 (p-H.sub.2 O), 264 (p-C.sub.4
H.sub.10 O), 251, 249, 237, 220, 121, 83, 49 (base peak); R.sub.f
=0.29. (system II).
B. Title compound TR4675 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to title compound
TR-4676 above; R.sub.f =0.24 (system II).
EXAMPLE 28
This example illustrates the preparation of:
A. 1-Acetoxy-15S-hydroxy-16,18-methanoprosta-10,13E-dien-9-one
(TR-4565); and
B. 1-Acetoxy-15R-hydroxy-16,18-methanoprosta-10,13E-dien-9-one
(TR-4568).
The mixture of partially protected forms of title compounds TR-4570
and TR-4569 separated in Example 23 above was stirred with 25 ml of
acetic acid-water tetrahydrofuran (65:35:10 V/V/V) under argon at
60.degree. C. for 18 hr. The solvent was removed by evaporation in
vacuo. The residue was dissolved in ethyl acetate and washed with
aqueous sodium bicarbonate. The resultant organic solution was
dried over anhydrous magnesium sulfate and the solvent evaporated
in vacuo. The residue was chromatographed on silicic acid-Celite
(85:15) using a benzene to ethyl acetate gradient elution to yield
the title compounds.
A. Title compound TR-4565 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, broad triplet, J=6.5
Hz), 1.0-2.3 (22H, multiplet), 2.07 (3H, singlet), 3.30 (1H, broad
singlet), 4.12 (2H, broad triplet, J=6.0 Hz), 3.8 (1H, multiplet),
5.68 (2H, multiplet), 6.23 (1H, d of d, J6 Hz, 2.5 Hz), and 7.6 ppm
(1H, d of d, J=6 Hz, 2.5 Hz); IR(film).nu.: 970, 1040, 1240, 1370,
1465, 1595, 1710, 1740, 2870, 2980, and 3200 to 3600 cm.sup.-1
(broad); Mass Spectrum (70 eV)m/e: 376 (strong p), 358 (p-H.sub.2
O), 348, 334 (p-C.sub.2 H.sub.3 O), 316 (p-C.sub.2 H.sub.3
o-H.sub.2 0), 293 (p-C.sub.6 H.sub.11), 351 (p-C.sub.6 H.sub.16
-C.sub.2 H.sub.3 O); Optical Rotation: [.alpha.].sub.D +89.degree.
(c 1.0, CHCl.sub.3).
B. Title compound TR-4568 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to TR-4565 above;
Optical Rotation [.alpha.].sub.D +100.3 (c 1.0, CHCl.sub.3).
EXAMPLE 29
This example illustrates the preparation of:
A. 16,18-Methanoprost-13E-en-1,9.alpha.,11.alpha.,15S-tetraol
(TR-4626); and
B. 16,18-Methanoprost-13E-en-1,9.beta.,11.alpha.,15S-tetraol
(TR-4627).
A solution of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene (2.194
g, 6.49 mmole; prepared in Example 1-J) in 50 ml of dry ether
(distilled from sodium benzophenone ketyl) was prepared and cooled
to -78.degree. C. To this solution there was added 7.29 ml of 1.78
M (12.98 mol) t-butyllithium in pentane and the mixture was stirred
for 2 hr at -78.degree. C. Copper (I) pentyne (1.844 g, 6.49 mol)
was slurried in 50 ml of dry ether and 2.24 ml of dry
hexamethylphosphorus triamide was added and the mixture was stirred
for 30 min and then cooled to -78.degree. C. To this copper reagent
solution there was then added the previously prepared organolithium
solution. A solution of methyl
7-[3.alpha.-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
heptanoate (2.034 g, 6.2 mol; preparation described in J. Amer.
Chem. Soc., 95:1696[1973]) in 4 ml of dry ether was slowly added to
the lithium dialkenyl cuprate solution prepared above. The
resultant mixture was stirred for 30 min at -78.degree. C., then
for 90 min at -20.degree. C. and then the mixture was quenched with
20% aqueous ammonium sulfate solution. This mixture was shaken for
10 min and the phases which formed were separated. The aqueous
phase was extracted with 100 ml (2.times.50 ml) of ether. The
organic phase was shaken with cold 2% aqueous sulfuric acid. This
acidified organic phase was then extracted with 100 ml (2.times.50
ml) of ether. The combined ether extracts were filtered through
Celite (diatomaceous earth). The filtrate was washed with 50 ml of
saturated sodium bicarbonate solution and then with 50 ml of
saturated aqueous sodium chloride solution. The washed extract was
dried over anhydrous magnesium sulfate and the solvent was removed
by evaporation in vacuo. The residue was stirred with 25 ml of
acetic acid-water tetrahydrofuran (65:35:10 V/V/V) for 18 hr at
room temperature. The solvents were removed in vacuo and the
residue was taken up in 30 ml of water and 30 ml of ether-ethyl
acetate (1:1 V/V). The aqueous material was separated and extracted
with 60 ml (2.times.30 ml ) of ether-ethyl acetate (1:1 V/V). This
extract and the separated organic material were combined and the
mixture was washed with 30 ml of saturated aqueous sodium
bicarbonate and then with 30 ml of saturated sodium chloride. The
washed material was then dried over anhydrous magnesium sulfate and
the solvent was removed by evaporation in vacuo. The residue was
chromatographed on silicic acid-Celite (85:15 W/W) using a
benzene-ethyl acetate gradient elution and the 15R-PGE.sub.1 isomer
was separated (Optical Rotation: [.alpha.].sub.D -39.8.degree.
[c1.0, CHCl.sub.3 ]). A solution containing 466 mg of this
separated isomer in 25 ml of methanol was prepared and stirred with
ice-bath cooling as 700 mg of sodium borohydride was added over 15
min. The resultant mixture was stirred with ice-bath cooling for
0.5 hr and then without cooling for 0.5 hr. Water was added to this
reaction mixture and the solvents were removed by evaporation in
vacuo. The residue was chromatographed on silicic acid-Celite
(85:15) to yield the title compounds.
A. Title compound TR-4626 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.95 (3H, broad triplet, J=6.5
Hz), 1.0 to 2.5 (24H,, multiplet), 2.7 (4H, broad singlet), 3.77
(2H, broad triplet, J=6 Hz), 4.02 (2H, broad multiplet), 4.23 (1H,
broad multiplet) and 5.62 (2H, multiplet); IR(CHCl.sub.3).nu.:
2860, 2930 and 3200 to 3600 cm.sup.-1 (broad); Mass Spectrum (70
eV)m/e: 336 (p-H.sub.2 O), 318 (p-2H.sub.2 O), 387, 292, 271
(p-C.sub.6 H.sub.11), 264, 253 (p-C.sub.6 H.sub.11 -H.sub.2 O);
Optical Rotation: [.alpha.].sub.D +8.5 (c 1.0, CHCl.sub.3).
B. Title compound TR-4627 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3), IR(CHCl.sub.3) and Mass Spectrum similar
to TR-4626 above; Optical Rotation: [.alpha.].sub.D -23.4.degree.
C. (c 1.0, CHCl.sub.3).
EXAMPLE 30
This example illustrates the preparation of:
A. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-9-oxoprost-13E-en-1-oate
(TR-4248); and
B. Methyl
11.alpha.,15S-dihydroxy-16,18-methano-9-oxoprost-13E-en-1-oate
(TR-4249).
A first solution containing (2.194 g, 6.49 mol) of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene
(prepared in Example 1 J) in 50 ml of dry ether (distilled from
sodium benzophenone ketyl) was prepared and cooled to -78.degree.
C. To this solution there was added 7.29 ml (12.98 mol, . . . 78 M)
of t-butyllithium in pentane and the resulting mixture was stirred
for 2 hr at -78.degree. C. A second solution containing 0.844 g
(6.49 mol) of copper (I) pentyne in 50 ml of dry ether and 2.24 ml
of dry hexamethylphosphorus triamide was prepared, stirred for 30
min and cooled to -78.degree. C. The second solution was then added
to the first solution. A third solution containing 2.035 g (6.2
mol) of methyl
7-[3.alpha.-tetrahydropyran-2-yloxy)-5oxocyclopent-1enyl]
heptanoate (preparation described in J. Amer. Chem. Soc., 95:1676
[1973]), in 4 ml of dry ether was prepared and added to the above
mixture of the first and second solutions. The resulting mixture
was stirred for 30 min at -78.degree. C., then 90 min at
-20.degree. C. and then quenched with 20% aqueous ammonium sulfate
solution. This mixture was shaken for 10 min and the phases were
separated. The aqueous phase was extracted with 100 ml (2.times.50
ml) of ether. The organic phase was shaken with cold 2% aqueous
sulfuric acid and the aqueous layer was then extracted with 100 ml
(2.times.50 ml) of ether. The organic extracts were combined and
filtered through Celite (diatomaceous earth), washed with 50 ml of
saturated aqueous sodium bicarbonate solution and then with 50 ml
of saturated aqueous sodium chloride solution. The washed extract
was dried over anhydrous magnesium sulfate and the solvent was
removed by evaporation in vacuo. The residue was stirred for 18 hr
with 25 ml of acetic acid-water-tetrahydrofuran (65:35:10, V/V/V)
at room temperature. The solvents were removed in vacuo and the
residue was taken up in 30 ml of water and 30 ml of ether-ethyl
acetate. The aqueous material was extracted with 60 ml (2.times.30
ml) of ether-ethyl acetate. The ether-ethyl acetate extract was
washed with 30 ml of saturated aqueous sodium bicarbonate and then
with 30 ml of saturated aqueous sodium chloride. The wash extract
was dried over anhydrous magnesium sulfate and the solvent was
removed by evaporation in vacuo. The residue was chromatographed on
silicic acid-Celite (85:15 W/W) using a benzene-ethyl acetate
gradient elution to yield the title compound TR-4249 and
TR-4248.
A. Title compound TR-4248 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8 (3H, triplet, J=6 Hz),
1.0-2.9 (24H, multiplet), 3.65 (3H, singlet), 3.8-4.3 (4H,
multiplet) and 5.65 ppm (2H, multiplet; IR(CHCl.sub.3).nu.:
3600-3100, 2950, 1740 cm.sup.-1 ; [.alpha.].sub.D -39.8.degree. (c
1.0, CHCl.sub.3).
B. Title compound TR-4249 had the following physical
characteristics:
Analysis--NMR(CHCl.sub.3): .delta.0.8 (3H, triplet, J=6 Hz),
1.0-3.3 (24H, multiplet), 3.65 (3H, singlet), 3.65-4.2 (4H,
multiplet) and 5.6 ppm (2H, multiplet); IR(CHCl.sub.3).nu.:
3600-3100, 2950, 1740 cm.sup.-1 ; [.alpha.].sub.D -49.6.degree. (c
0.96, CHCl.sub.3).
EXAMPLE 31
This example illustrates the preparation of:
A. Methyl
11.alpha.,15S-dihydroxy-16,18-methano-16-methyl-9-oxoprost-13E-en-1-oate
(TR-4682); and
B. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-16-methyl-9-oxoprost-13E-en-1-oate
(TR-4681).
Repeating in a similar manner the procedure of Example 30 but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethyl-1-methylcyclobutyl)-1E-propene
(prepared in Example 8A) yield the above title compounds.
A. Title compound TR-4682 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.8 (3H, broad triplet, J=6.5
Hz), 1.03 and 1.11 (3H, total, two singlets, isomeric methyl on
C-16), 1.0 to 3.3 (23H, multiplet), 3.70 (3H, singlet), 4.02 (3H,
multiplet), 4.23 (1H, multiplet), and 5.80 (2H, multiplet);
IR(CHCl.sub.3).nu.: 970, 1075, 1165, 1230, 1740, 2860, 2930, 2960
and 3200 to 3600 cm.sup.-1 ; Mass Spectrum (70 eV)m/e: 376
(p-H.sub.2 O), 358 (p-2H.sub.2 O), 345 (p-H.sub.2 O-CH.sub.3 O),
327 (p-2H.sub.2 O-CH.sub.3 O), 297 (p-C.sub.7 H.sub.13), 279
(p-H.sub.2 O-C.sub.7 H.sub.13); Optical Rotation: [.alpha.].sub.D
-65.9.degree. (c 1.0, CHCl.sub.3).
B. Title compound TR-4681 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to title compound
TR-4682 above; Optical Rotation: [.alpha.].sub.D -54.3.degree. (c
0.81, CHCl.sub.3).
EXAMPLE 32
This example illustrates the preparation of:
A. Methyl
16,19-cyclo-11.alpha.,15S-dihydroxy-16-methyl-20-nor-9-oxoprost-13E-en-1-o
ate (TR-4691); and
B. Methyl
16,19-cyclo-11.alpha.,15R-dihydroxy-16-methyl-20-nor-9-oxoprost-13E-en-1-o
ate (TR-4690).
Repeating in a similar manner the procedure of Example 32, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(1-methylcyclobutyl)-1E-propene
(prepared in Example 8B) yields the above title compounds.
A. Title compound TR-4691 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.13 (3H, singlet), 1.0 to 3.3
(22H, multiplet), 3.73 (3H, singlet), 4.2 (4H, multiplet), and 5.83
ppm (2H, multiplet); IR(CHCl.sub.3).nu.: 975, 1080, 1170, 1230,
1440, 1740, 2870, 2950 and 3200 to 3600 cm.sup.-1 (broad); Mass
Spectrum (70 e/V)m/e: 348 (p-H.sub.2 O), 330 (p-2H.sub.2 O), 316
(p-H.sub.2 O-CH.sub.3 OH), 299 (p-2H.sub.2 O-CH.sub.3 O), 297
(p-C.sub.5 H.sub.9), 279 (p-H.sub.2 O-C.sub.5 H.sub.9); Optical
Rotation: [.alpha.].sub.D -65.5.degree. (c 1.10, CHCl.sub.3).
B. Title compound TR-4690 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to title compound
TR-4691 above; Optical Rotation [.alpha.].sub.D -50.4.degree. (c
1.39, CHCl.sub.3).
EXAMPLE 33
This example illustrates the preparation of:
A. Methyl
11.alpha.,15S-dihydroxy-9-oxo-16-,16-propanoprost-13E-en-1-oate
(TR-4677); and
B. Methyl
11.alpha.,15R-dihydroxy-9-oxo-16,16-propanoprost-13E-en-1-oate
(TR-4692).
Repeating in a similar manner the procedure of Example 32, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(1-butylcyclobutyl)-1E-propene
(prepared in Example 8C) yields the above title compounds.
A. Title compound TR-4677 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .alpha.0.8 (3H, broad triplet, J=6.5
Hz), 1.0-3.2 (28H, multiplet), 3.71 (3H, singlet), 4.18 (4H,
multiplet) and 5.83 ppm (2H, multiplet); IR(CHCl.sub.3).nu.: 970,
1070, 1160, 1230, 1440, 1740, 2860, 2930 and 3200 to 3600 cm.sup.-1
(broad); Mass Spectrum (70 eV)m/e: 390 (p-H.sub.2 O), 372
(p-2H.sub.2 O), 341 (p-2H.sub.2 O-OMe), 319, 297 (p-C.sub.8
H.sub.15), 280, 279, 265, 247, 191, 99, 69 (base peak, C.sub.5
H.sub.9); Optical Rotation [.alpha.].sub.D -82.1.degree. (c 1.15,
CHCl.sub.3).
B. Title compound TR-4692 had the following physical
characteristics:
Analysis--NMR, IR and Mass Spectrum similar to title compound
TR-4677 above; Optical Rotation: [.alpha.].sub.D -61.3.degree. (c
1.13, CHCl.sub.3).
EXAMPLE 34
This example illustrates the preparation of:
A. Methyl 15RS-hydroxy-16,18-methano-9-oxoprosta-10,13E-dien-1-oate
(TR-4280); and
B. Methyl 15RS-acetoxy-16,18-methano-9-oxoprosta-10,13E-dien-1-oate
(TR-4281).
A solution of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene
(prepared in Example 1J) (2.194 g, 6.49 mol) in 50 ml of dry ether
(distilled from sodium benzophenone ketyl) was prepared and cooled
to -78.degree. C. To this solution, there was added t-butyllithium
in pentane (7.29 ml, 12.98 mmol, 1.78 M) and the mixture was
stirred for 2 hr at -78.degree. C. Copper(I) pentyne (0.844 g, 6.49
mmol) was slurried in 50 ml of dry ether and 2.24 ml of dry
hexamethylphosphorus triamide was added and the mixture was stirred
for 30 min and then cooled to -78.degree. C. The organolithium
solution was then added to this copper reagent solution. A solution
of methyl
7-[3.alpha.-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
heptanoate (preparation described in J. Amer. Chem. Soc., 95:1676
[1973]) (2.035 g, 6.2 mmol) in 4 ml of dry ether was slowly added
to the lithium dialkenyl cuprate solution and the resulting mixture
was stirred for 30 min at -78.degree. C., 90 min at -20.degree. C.
and then was quenched with 20% aqueous ammonium sulfate solution.
The mixture was shaken for 10 min and the phases which formed were
separated. The aqueous phase was extracted with 100 ml (2.times.50
ml of ether. The organic phase was shaken with cold 2% aqueous
sulfuric acid. This acidic aqueous phase was then extracted with
100 ml (2.times.50 ml) of ether. The ether extracts were combined
and filtered through Celite (diatomaceous earth). The filtrate was
washed with 50 ml of saturated sodium bicarbonate solution and then
with 50 ml of saturated aqueous sodium chloride solution. The
washed extract was dried over anhydrous magnesium sulfate and the
solvent was removed by evaporation in vacuo. The residue was
stirred with 25 ml of acetic acid-wafter-tetrahydrofuran (65:35:10
V/V/V) for 18 hr at room temperature. The solvents were removed in
vacuo and the residue was taken up in 30 ml of water and 30 ml of
ether-ethyl acetate (1:1 V/V). The aqueous material was extracted
with 60 ml (2.times.30 ml) of ether-ethyl acetate (1:1 V/V). This
extract and the organic material were combined and washed with 30
ml of saturated aqueous sodium bicarbonate and then with 30 ml of
saturated sodium chloride. The washed material was then dried over
anhydrous magnesium sulfate and the solvent was removed by
evaporation in vacuo. The residue (0.128 g) was taken up with 3 ml
of glacial acetic acid and 0.5 ml of water and stirred at
60.degree. C. for 18 hr. This mixture was cooled and the solvents
were removed in vacuo. The resulting residue was taken up in 10 ml
of water and 20 ml of ether-ethyl acetate (1:1 V/V) and the phases
which formed were separated. The aqueous phase was extracted with
40 ml (2.times.20 ml) of ether-ethyl acetate (1:1 V/V). The
ether-ethyl acetate extract was combined with the organic phase and
the mixture was washed with 20 ml of saturated aqueous sodium
bicarbonate and then with 20 ml of saturated aqueous sodium
chloride. The washed mixture was dried over anhydrous magnesium
sulfate and the solvent was removed by evaporation in vacuo. The
residue was chromatographed on a column of silicic acid-Celite
(85:15 W/W) using a benzene-ethyl acetate gradient elution to yield
the title compounds.
A. Title compound TR-4280 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9 (3H, triplet, J=6 Hz),
0.8-2.8 (22H, multiplet), 3.3 (1H, multiplet), 3.75 (3H, singlet),
4.1 (1H, multiplet) 5.6 (2H, multiplet), 6.2 (1H, multiplet) and
7.6 ppm (1H, multiplet); IR(CHCl.sub.3).nu.: 2950, 1730, 1710
cm.sup.-1.
B. Title compound TR-4281 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9 (3H, triplet, J=6 Hz),
0.7-2.6(22H, multiplet), 2.2 (3H, singlet), 3.3 (1H, multiplet),
3.8 (3H, singlet), 5.7 (2H, multiplet), 6.3 (1H, multiplet), and
7.5 ppm (1H, multiplet); IR(CHCl.sub.3).nu.: 2950, 1750, 1730, 1710
cm.sup.-1.
EXAMPLE 35
This example illustrates the preparation of:
A. Methyl
16,19-cyclo-15S-hydroxy-16-methyl-20-nor-9-oxoprosta-10,13E-dien-1-oate
(TR-4684); and
B. Methyl
16,19-cyclo-15R-hydroxy-16-methyl-20-nor-9-oxoprosta-10,13E-dien-1-oate
(TR-4683).
Repeating in a similar manner the procedure of Example 34, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(1-methylcyclobutyl)-1E-propene
(prepared in Example 8B) yields the title compounds.
A. Title compound TR-4884 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.13 (3H, singlet), 1.2 to 2.8
(20H, multiplet), 3.4 (1H, multiplet), 3.77 (3H, singlet), 4.15
(1H, multiplet), 5.8 (2H, multiplet), 6.38 (1H, multiplet) and 7.7
ppm (1H, multiplet); IR(CHCl.sub.3).nu.: 970, 1170, 1440, 1705,
1730, 2860, 2940 and 3200 to 3600 cm.sup.-1 (broad); Mass Spectrum
(70 eV)m/e:348 (p), 330(p-H.sub.2 O), 316(p-CH.sub.3 OH),
298(p-H.sub.2 O-CH.sub.3 OH), 279 (p-C.sub.5 H.sub.9),
261(p-H.sub.2 O-C.sub.5 H.sub.9); Optical Rotation: [.alpha.].sub.D
+96.0.degree. (c 1.08,CHCl.sub.3).
B. Title compound TR-4683 had the following physical
characteristics:
Analysis--NMR,IR and Mass Spectrum similar to title compound
TR-4684 above; Optical Rotation: [.alpha.].sub.D +97.9.degree. (c
0.95,CHCl.sub.3).
EXAMPLE 36
This example illustrates the preparation of:
A. Methyl
15S-hydroxy-16,18-methano-16-methyl-9-oxoprosta-10,13E-dien-1-oate
(TR-469 5); and
B. Methyl
15R-hydroxy-16,18-methano-16-methyl-9-oxoprosta-10,13E-dien-1-oate
(TR-469 4).
Repeating in a similar manner the procedure of Example 34, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethocy)-3-(1-methyl-3-ethylcyclobutyl)-1E-propene
(prepared in Example 8A) yields the title compound.
A. Title compound TR-4694 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.80 (3H, triplet, J=7.0 Hz),
1.07 and 1.13 (3H, total, 2 singlets, isomers), 1.0 to 2.7 (21H,
multiplet), 3.30 (1H, multiplet), 3.73 (3H, singlet), 4.0 (1H,
multiplet), 5.76 (2H, multiplet), 6.30 (1H, multiplet) and 7.63 ppm
(1H, multiplet); IR(CHCl.sub.3).nu.: 970, 1090, 1170, 1220, 1370,
1430, 1455, 1700, 1725, 2850, 2920, 3460 (broad) and 3600 cm.sup.-1
; Mass Spectrum (70 eV)m/e:376 (p),358, 326, 325, 297, 296, 278,
261, 246 (base), 229; Optical Rotation: [.alpha.].sub.D
+96.8.degree.(c 0.94,CHCl.sub.3).
B. Title compound TR-4695 had the following physical
characteristics:
Analysis--NMR,IR and Mass Spectrum similar to title compound
TR-4694 above; Optical Rotation: [.alpha.].sub.D +81.degree. (c
1.07,CHCl.sub.3).
EXAMPLE 37
This example illustrates the preparation of:
A. Methyl
16,18-methano-9.alpha.,1.alpha.,15S-trihydroxyprost-13E-en-1-oate
(TR-4624); and
B. Methyl
16,18-methano-9.beta.,11.alpha.,15S-trihydroxyprost-13E-en-1-oate
(TR-4625).
A solution of
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene (2.194
g. 6.49 mmol; prepared in Example 1J) in 50 ml of dry ether
(distilled from sodium benzophenone ketyl) was prepared and cooled
to -78.degree. C. To this solution there was added 7.29 ml of 1.78
M (12.98 mmol) t-butyllithium in pentane and the mixture was
stirred for 2 hr at -78.degree. C. Copper (I) pentyne (0.844 g,
6.49 mmol) was slurried in 50 ml of dry ether and 2.24 ml of dry
hexamethylphosphorus triamide was added and the mixture was stirred
for 30 min and then cooled to -78.degree. C. To this copper reagent
solution there was then added the previously prepared organolithium
solution. A solution of methyl
7-[3.alpha.(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]
heptanoate (2.035 g. 6.2 mmol; preparation described in J. Amer.
Chem. Soc., 95:1696 [1973] ) in 4 ml of dry ether was slowly added
to the lithium dialkenyl cuprate solution prepared above. The
resulting mixture was stirred for 30 min at -78.degree. C., then
for 90 min at -20.degree. C. and then the mixture was quenched with
20% aqueous ammonium sulfate solution. This mixture was shaken for
10 min and the phases which formed were separated. The aqueous
phase was extracted with 100 ml (2.times.50 ml) of ether. The
organic phase was shaken with cold 2% aqueous sulfuric acid. This
acidic aqueous phase was then extracted with 100 ml (2.times.50 ml)
of ether. The combined ether extracts were filtered through Celite
(diatomaceous earth). The filtrate was washed with 50 ml of
saturated sodium bicarbonate solution and then with 50 ml of
saturated aqueous sodium chloride solution. The washed extract was
dried over anhydrous magnesium sulfate and the solvent was removed
by evaporation in vacuo. The residue was stirred with 25 ml of
acetic acid-water-tetrahydrofuran (65:35:10 V/V/V) for 18 hr at
room temperature. The solvents were removed in vacuo and the
residue was taken up in 30 ml of water and 30 ml of ether-ethyl
acetate (1:1 V/V). This extract and the separated organic material
were combined and the mixture was washed with 30 ml of saturated
aqueous sodium bicarbonate and then with 30 ml of saturated sodium
chloride. The washed material was then dried over anhydrous
magnesium sulfate and the solvent was removed by evaporation in
vacuo. The residue was chromatographed on silicic acid-Celite
(85:15 W/W) using a benzene-ethyl acetate gradient elution and the
15R-PGE.sub.1 isomer was separated (Optical Rotation:
[.alpha.].sub.D -39.8.degree.[c1.0,CHCl.sub.3 ]). A solution
containing 466 mg of this separated isomer in 25 ml of methanol was
prepared and stirred with ice-bath cooling as 700 mg of sodium
borohydride was added over 15 min. The resultant mixture was
stirred with ice-bath cooling for 0.5 hr and then without cooling
for 0.5 hr. Water was added to this reaction mixture and the
solvents were removed by evaporation in vacuo. The residue was
mixed with water and extracted four times with ethyl acetate. The
combined ethyl acetate extract was dried over anhydrous magnesium
sulfate and evaporated in vacuo. The residue was chromatographed on
silicic acid-Celite (85:15) to yield the title compounds.
A. Title compound TR-4624 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.77 (3H, broad triplet, J=6.5
Hz), 1.0-2.7 (24H, multiplet), 2.65 (3H, broad singlet), 3.7 (3H,
singlet), 4.01 (2H, broad multiplet), 4.23 (1H, broad multiplet)
and 5.6 ppm (2H, multiplet); IR(CHCl.sub.3).nu.: 1740, 2950 and
3200 to 3600 cm.sup.-1 (broad); Mass Spectrum (70 eV)m/e:382(p,
weak), 364(p-H.sub.2 O), 346(p-2H.sub.2 O), 333(p-H.sub.2
O-CH.sub.3 O), 315(p-2H.sub.2 O-CH.sub.3 O), 299 (p-C.sub.6
H.sub.11), 292, 281(p-H.sub.2 O-C.sub.6 H.sub.11), 263,249,236,221;
Optical Rotation: [.alpha.].sub.D +7.0(c 1.0,CHCl.sub.3).
B. Title compound TR-4625 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.77 (3H, broad triplet, J=6.5
Hz), 1.0-2.7 (24H, multiplet), 3.5 (3H, singlet), 3.7 (3H,
singlet), 4.02 (3H, broad multiplt) and 5.61 ppm (2H, multiplet);
IR and Mass Spectrum similar to TR-4624 above; Optical Rotation:
[.alpha.].sub.D -21.0.degree. (c 1.0,CHCl.sub.3).
EXAMPLE 38
This example illustrates the preparation of:
A. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-20,20-propano-9-oxoprost-13E-en-1-oa
te (TR-4796); and
B. Methyl
11.alpha.,15S-dihydroxy-16,19-methano-20,20-propano-9-oxoprost-13E-en-1-oa
te (TR-4797)
Repeating in a similar manner the procedure of Example 30, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-[3-(cyclobutylmethyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-iodoprop-2-
ene (prepared in Example 21B) yields the title compounds.
A. Title compound 4796 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.65 (s,3H), 3.2-4.2 (complex,
4H) and 5.50 (complex, 2H); IR(CHCl.sub.3) .lambda..sub.max : 2.78,
2.95 (broad), 5.75, 6.95 and 10.40.mu.; Mass Spectrum (70
eV)m/e:402(p-H.sub.2 O), 384(p-2H.sub.2 O) and 271(p-H.sub.2
O-OCH.sub.3); Optical Rotation: [.alpha.].sub.D -32.1.degree. (c
1.0,CHCl.sub.3).
B. Title compound 4797 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.65 (s, 3H), 3.8-4.2 (complex,
2H) and 5.65 (complex, 2H); IR(CHCl.sub.3) .lambda..sub.max : 2.78,
2.90 (broad), 5.75 and 10.4.mu.; Mass Spectrum: essentially same as
TR-4796 above; Optical Rotation: [.alpha.].sub.D -57.4.degree. (c
0.73,CHCl.sub.3).
EXAMPLE 39
This example illustrates the preparation of:
A.
1,11.alpha.,15R-Trihydroxy-16,18-methano-20,20-propanoprost-13E-en-9-one
(TR-4832); and
B.
1,11.alpha.,15S-Trihydroxy-16,18-methano-20,20-propanoprost-13E-en-9-one
(TR-4833).
Repeating in a similar manner the procedure of Example 23, but
replacing
1-iodo-3-(1-ethoxyethoxy)-3-(3-ethylcyclobutyl)-1E-propene with
1-[3-(cyclobutylmethyl)-cyclobutyl]-1-(1-ethoxyethoxy)-trans-3-iodoprop-2-
ene (prepared in Example 21B) yields the title compounds.
A. Title compound 4832 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.65 (t,J=5.0 Hz,2H), 3.20 (broad
s, 3H), 3.92 (complex, 3H) and 5.56 (complex, 2H); IR(CHCl.sub.3)
.lambda..sub.max : 2.78, 2.90 (broad), 5.75 and 10.4.mu.; Mass
Spectrum (70 eV)m/e:374(p-H.sub.2 O) and 356(p-2H.sub.2 O); Optical
Rotation: [.alpha.].sub.D -57.2.degree.(c 0.76,CHCl.sub.3).
B. Title compound 4833 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.65 (t,J=5.0 Hz, 2H), 4.00
(complex, 2H) and 5.65 (complex, 2H); IR(CHCl.sub.3)
.lambda..sub.max : 2.78, 2.92 (broad), 5.75, 9.25 and 10.4.mu.;
Mass Spectrum: essentially same as TR-4832 above; Optical Rotation:
[.alpha.].sub.D -66.3.degree.(c 0.93,CHCl.sub.3).
EXAMPLE 40
This example illustrates the preparation of:
A.
1,11.alpha.,15S-Trihydroxy-16,18-methano-19,20-ethanoprost-13E-en-9-one
(TR-4880); and
B.
1,11.alpha.,15R-Trihydroxy-16,18-methano-19,20-ethanoprost-13E-en-9-one
(TR-4881).
Repeating in a similar manner the procedure of Example 23, but
replacing
1-iodo-3-(1-ethoxyethoxy)-2-(3-ethylcyclobutyl)-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(3-cyclobutyl) cyclobutyl-1E-propene
(prepared in Example 42) yields the title compounds.
A. Title compound 4881 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.33 (broad s, 3H), 3.62 (t,J=6.0
Hz, 2H), 3.90 (complex, 2H) and 5.56 (complex, 2H); IR(CHCl.sub.3)
.lambda..sub.max : 2.78, 2.90 (broad), 5.75 and 10.4.mu.; Mass
Spectrum (70 eV)m/e: 360(p-H.sub.2 O), 342(p-2H.sub.2 O) and
332(p-H.sub.2 O-C.sub.2 H.sub.4); Optical Rotation: [.alpha.].sub.D
-43.4.degree.(c 1.2,CHCl.sub.3).
B. Title compound 4880 had the following physical
characteristics:
Analysis--NMR(CHCl.sub.3): .delta.3.63 (t,J=6.0 Hz, 2H), 3.96
(complex, 2H) and 3.66 (complex, 2H); IR and Mass Spectrum:
essentially same as TR-4881 above; Optical Rotation:
[.alpha.].sub.D -53.6.degree.(c 0.75,CHCl.sub.3).
EXAMPLE 41
This example illustrates the preparation of:
A. Methyl
11.alpha.,15R-dihydroxy-16,18-methano-19,20-ethano-9-oxoprost-13E-en-1-oat
e (TR-4882); and
B. Methyl
11.alpha.,15S-dihydroxy-16,18-methano-19,20-ethano-9-oxoprost-13E-en-1-oat
e (TR-4887).
Repeating in a similar manner the procedures of Example 30, but
replacing 1-iodo-3-(1-ethoxyethoxy)-3-(3-ethyl)
cyclobutyl-1E-propene with
1-iodo-3-(1-ethoxyethoxy)-3-(3-cyclobutyl) cyclobutyl-1E-propene
(prepared in Example 42) yields the title compounds.
A. Title compound 4882 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.66 (s, 3H), 4.00 (complex, 4H)
and 5.53 (complex, 2H); IR(CHCl.sub.3) .lambda..sub.max : 2.90
(broad), 5.75, 6.95 and 10.4.mu.; Mass Spectrum (70 eV)m/e:
370(p-H.sub.2 O), 357(p-2H.sub.2 O) and 339(p-H.sub.2 O-C.sub.2
H.sub.4); Optical Rotation: [.alpha.].sub.D -57.2.degree.(c
1.2,CHCl.sub.3).
B. Title compound 4887 had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.66 (s, 3H), 4.00 (complex, 2H)
and 4.67 (complex, 2H); IR(CHCl.sub.3) .lambda..sub.max : 2.78,
2.90 (broad), 5.75, 6.99 and 10.4.mu.; Optical Rotation:
[.alpha.].sub.D -43.8.degree.(c 0.99,CHCl.sub.3).
EXAMPLE 42
This example illustrates the preparation of
1-iodo-3-(1-ethoxyethoxy)-3-(3-cyclobutyl)
cyclobutyl-1E-propene.
A. Preparation of Cyclobutane carbinol
A slurry of 21.0 g (0.55 moles) of lithium aluminum hydride (LAH)
in 500 ml ether was stirred under argon at 0.degree. C. and a
solution of 50.0 g of cyclobutane-carboxylic acid in 250 ml ether
added dropwise. The reaction mixture was refluxed for 2.0 hr. The
reaction mixture was cooled to 0.degree. C. and 75 ml of ethyl
acetate cautiously added, followed successively by 21 ml H.sub.2 O,
21 ml of 15% NaOH, and 45 ml of H.sub.2 O. The resultant mixture
was stirred for 0.5 hr at 25.degree. C. and then filtered. The
residue was washed with ether. The filtrate was washed with brine,
then dried (MgSO.sub.4) and filtered. Product was isolated by
distillation (aspirator vacuum) to yield 24.4 g of the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.55 (d,J=7.0H.sub.2, 2H);
IR(CHCl.sub.3).nu.: 3600, 3450 (broad) and 1020 cm.sup.-1 ; bp
55.degree.-60.degree. C.
B. Preparation of (p-Toluenesulfonyloxy) (cyclobutyl) methane
A solution of 24.4 g of Cyclobutane carbinol (prepared in Example
42A) in 570 ml of dry pyridine was stirred under argon at
-10.degree. C. and 81.0 g of tosyl chloride added in small
portions. The reaction mixture was stirred at -10.degree. C. to
-0.degree. C. for 4.5 hr, then poured into 1 liter of chilled 6 N
HCl. The layers were separated and the aqueous layer extracted with
ether-ethyl acetate. The combined extracts were washed with 10%
aqueous sodium bicarbonate (NaHCO.sub.3), dried (MgSO.sub.4),
filtered and evaporated in vacuo to yield 72.0 g of the title
compound having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.2.42 (s, 3H), 4.0 (d,J=7.0 Hz,
2H), 7.35 (d,J=7.0 Hz, 2H), 7.35 (d,J=9.0 Hz, 2H) and 7.80 (d,J=9.0
Hz, 2H); IR(CHCl.sub.3).nu.: 1600, 1260, 1170 and 1090 cm.sup.-1 ;
no 3600 or 3450 cm.sup.-1 signals observed.
C. Preparation of Cyclobutyl Acetonitrile
A solution of 68.0 g of (p-Toluenesulfonyloxy) (cyclobutyl) methane
(prepared in Example 42B) and 22.0 g of sodium cyanide in 450 ml of
dry dimethyl sulfoxide was stirred and heated to 100.degree. C. for
18.0 hr under argon. The reaction mixture was cooled to 0.degree.
C. and poured into 400 ml of 20% aqueous NH.sub.4 Cl. The aqueous
layer was extracted with 1:1 ether-hexane. The combined extracts
were washed with water, dried (Na.sub.2 SO.sub.4), filtered, and
evaporated at 25.degree. C. to yield 22.6 g of the title compound
having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.2.4(d,J=5.0 Hz, 2H);
IR(CHCl.sub.3).nu.: 2250 cm.sup.-1.
D. Preparation of Cyclobutyl acetic acid
A 2 liter, 3-necked, round-bottom flask was equipped with a reflux
condenser, mechanical stirring, serum cap, and a long needle (used
as an argon inlet). A solution of 22.6 g of Cyclobutyl acetonitrile
(prepared in Example 42C) in 480 ml of 95% ethanol and 450 ml of
30% aqueous hydrogen peroxide was added to the reaction vessel and
stirred at 50.degree. C. while argon was passed through the
solution for 5.0 hr. The reaction mixture was cooled to 0.degree.
C. and brine added to the solution, followed by sodium chloride.
The mixture was acidified with 6 N HCl, and extracted with 1:1
ether-ethyl acetate. The combined extracts were washed with brine,
dried (MgSO.sub.4), filtered and evaporated in vacuo to afford 22.9
g of the title compound having the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.2.50 (d,J=3.0 Hz, 2H) and 8.2
(broad s, 1H); IR(CHCl.sub.3).nu.: 3500, 3600-2400(broad), 1700 and
1600 cm.sup.-1 ; mp 148.degree.-149.degree. C.
E. Preparation of Ethyl cyclobutyl acetate
A solution of 22.9 g of cyclobutyl acetic acid (prepared in Example
42D) in 46 ml of absolute ethanol was stirred under argon at
25.degree. C. and 9.30 ml of conc. H.sub.2 SO.sub.4 added. The
reaction mixture was refluxed under argon for 16.0 hr. The reaction
mixture was cooled to 25.degree. C. and diluted with ether. The
ether layer was washed with water and 1 N aqueous K.sub.2 CO.sub.3,
dried (MgSO.sub.4), filtered and isolated by distillation
(aspirator vacuum) to yield 19.9 g. of the title compound having
the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.22(t,J=7.0 Hz, 3H), 2.40
(d,J=6.0 Hz, 2H) and 4.10(q,J=7.0 Hz, 2H); IR(CHCl.sub.3):
.nu.1725, 1450, 1380 and 1030 cm.sup.-1 ; bp 60.degree.-65.degree.
C.
F. Preparation of Ethyl 2-cyclobutyl malonate
A solution of 10.2 ml of diisopropyl amine in 83.0 ml of dry THF
was cooled to 0.degree. C. with stirring under argon and 40.0 ml of
2.3 M n-butyllithium in hexane injected dropwise. After 15.0 min at
0.degree. C., the reaction mixture was cooled to -78.degree. C. and
a solution of 11.6 g of ethyl cyclobutyl acetate (prepared in
Example 42E) in 43.0 ml of THF added dropwise. After 15 min at
-78.degree. C., a solution of 7.70 ml of ethyl chloroformate in 3.3
ml of THF was added to the reaction mixture. The reaction mixture
was stirred for 1.5 hr at -78.degree. C. The reaction mixture was
partitioned between 20% aqueous NH.sub.4 Cl and ether. The ether
layer was washed with brine, then dried (MgSO.sub.4), filtered and
isolated by distillation (oil pump vacuum) to yield 7.49 g of the
title compounds having the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.23(t,J=7.0 Hz, 3H),
3.36(d,J=10.0 Hz, 1H) and 4.18(q,J=7.0 Hz, 2H); bp
66.degree.-70.degree. C.
G. Preparation of 2-Cyclobutyl-propane-1,3-diol
The title compound was prepared according to the procedure of
Example 1A by replacing diethyl ethylmalonate with ethyl
2-cyclobutyl malonate (prepared in Example 42F). The resulting
product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.3.2-4.2 (complex, 6H), and
1.4-2.5 (complex, 8H); IR(CHCl.sub.3).nu.: 3610 and 3400 (broad)
cm.sup.-1 ; bp 90.degree.-95.degree. C.
H. Preparation of 2-Cyclobutyl-1,3-ditosyloxypropane
The title compound was prepared according to the procedure of
Example 1B by replacing 2-ethylpropane-1,3-dial with
2-cyclobutyl-propane-1,3-dial (prepared in Example 42G). The
resulting product had the follow physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.2.42 (s, 2H), 3.92 (broad t, 4H),
7.35 (d,J=9.0 Hz, 2H) and 7.75 (d,J=9.0 Hz, 2H);
IR(CHCl.sub.3).nu.: 1600, 1360, 1180, 1090 and 1000 cm.sup.-1.
I. Preparation of 1,1-Bis ethoxy-carbonyl-3-cyclobutyl
cyclobutane
The title compound was prepared according to the procedure of
Example 1C by replacing 2-ethyl-propyl-1,3-ditosylate with
2-cyclobutyl-1,3-ditosyloxypropane (prepared in Example 42H), the
resulting product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.22 (t,J=7.0 Hz, 6H) and
4.20(q,J=7.0 Hz, 4H); IR(CHCl.sub.3): .nu.1720, 1370, 1270, 1020
and 860 cm.sup.-1 ; bp 125.degree.-129.degree. C.
J. Preparation of 3-cyclobutyl-cyclobutane-1,1-dicarboxylic
acid
The title compound was prepared according to the procedure of
Example 1D replacing 3-ethyl-1,1-dicarbethoxycyclobutane with
1,1-bis-ethoxy-carbonyl-3-cyclobutyl (prepared in Example 42I). The
resulting product had the following physical characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.3-3.0 (complex 12H), 9.7 (broad
s, 2H); IR(CHCl.sub.3): .nu.3600, 2400, 1700, 1410 and 1290
cm.sup.-1 ; mp 150.degree.-151.degree. C.
K. Preparation of 3-Cyclobutyl-cyclobutane-1-carboxylic acid
The title compound was prepared according to the procedure of
Example 1E by replacing 3-ethylcyclobutane-1,1-dicarboxylic acid
with 3-cyclobutyl-cyclobutane-1,1-dicarboxylic acid (prepared in
Example 42J). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2-2.6 (complex, 12H), 2.9
(complex, 1H), 11.2 (broad s, 1H); IR(CHCl.sub.3): .nu.3400-2300,
1700, and 1420 cm.sup.-1 ; bp 91.degree.-93.degree. C.
L. Preparation of 3-Cyclobutyl-cyclobutane-1-carboxylic acid
chloride
The title compound was prepared according to the procedure of
Example 1F by replacing 3-ethylcyclobutane carboxylic acid with
3-cyclobutyl-cyclobutane-1-carboxylic acid (prepared in Example
42K). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.3-3.0 (complex, 12H), 3.5
(complex, 1H), no CO.sub.2 H signal observed; IR(CHCl.sub.3):
.nu.1790 and 1060 cm.sup.-1 ; bp 43.degree.-45.degree. C.
M. Preparation of (3-Cyclobutyl-cyclobutyl) (2-chlorovinyl)
ketone
The title compound was prepared using the procedure of Example 1G
by replacing 3-ethylcyclobutane carboxylic acid chloride with
3-cyclobutyl-cyclobutane-1-carboxylic acid chloride (prepared in
Example 42L). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.3-2.9 (complex, 12H), 3.2
(complex, 1H), 6.42 (d,J=14.0 Hz), 1H) and 7.25 (d,J=14.0 Hz, 1H);
IR(CHCl.sub.3): .nu.1670, 1490 and 935 cm.sup.-1 ; bp
75.degree.-80.degree. C.
N. Preparation of (3-Cyclobutyl-cyclobutyl) (2-iodovinyl)
ketone
The title compound was prepared using the procedure of Example 1H
by replacing 3-ethylcyclobutyl-trans-.beta.-chlorovinyl ketone with
(3-cyclobutyl-cyclobutyl)(2-chlorovinyl) ketone (prepared in
Example 42M). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.3-2.7 (complex, 12H) 7.08
(d,J=16.0 Hz, 1H) and 7.80 (d,J=16.0 Hz, 1H).
O. Preparation of
1-Iodo-3-(3-cyclobutyl-cyclobutyl)-3RS-hydroxy-1E-propene
The title compound was prepared using the procedure of Example II
by replacing 3-ethylcyclobutyl-trans-.beta.-iodovinyl ketone with
(3-cyclobutyl-cyclobutyl)(2-iodovinyl) ketone (prepared in Example
42N). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.0.9-2.8 (complex, 14H), 4.0
(complex, 1H), 6.40 (complex, 2H); IR(CHCl.sub.3): .nu. 3600, 3450
(broad), 1610, 940 cm.sup.-1.
P. Preparation of
1-Iodo-3-(3-cyclobutyl-cyclobutyl)-3RS-(1-ethoxy)ethoxy-1E-propene
The title compound was prepared using the procedure of Example 1J
by replacing 1-(3-ethylcyclobutyl)-trans-3-iodoprop-2-en-1-ol with
1-iodo-3-(3-cyclobutyl-cyclobutyl)-3RS-hydroxy-1E-propene (prepared
in Example 42-0). The resulting product had the following physical
characteristics:
Analysis--NMR(CDCl.sub.3): .delta.1.2 (t,J=8.0 Hz, 3H), 1.28
(d,J=8.0 Hz, 3H), 3.6 (complex, 4H), 4.68 (q,J=8.0 Hz, 1H), 6.35
(complex, 2H); IR(CHCl.sub.3): .nu. 1610, 1450, 945 cm.sup.-1.
EXAMPLE 43
A. Evaluation of Inhibition of Human Platelet Aggregation by
Analogs of Prostaglandins Structure III
The ability of test compounds to inhibit platelet aggregation was
determined by a modification of the turbidimetric technique of Born
(Nature, 194:927 [1962]). Blood was collected from human volunteer
who had not ingested aspirin or aspirin-containing products within
the preceding two weeks in heparinized containers and was allowed
to settle for one hr. The platelet rich plasma (PRP) supernates
were collected and cooled. Siliconized glassware was used
throughout.
In a representative assay 1.9 ml of PRP and 0.2 ml of test compound
at the appropriate concentrations (0.001 to 100 mcgm), or 0.2 ml of
distilled water (control procedure) were placed in sample cuvettes.
The cuvettes were placed in a 37.degree. C. incubation block for 15
min, and then in a spectrophotometer linked to a strip chart
recorder. After 30 to 60 seconds, 0.2 ml of a solution, prepared by
diluting a calf-skin collagen solution 1:9 with Tyrodes' Solution,
was added to each cuvette. Platelet aggregation was evidenced by a
decrease in optical density.
Calculation of the degree of inhibition of platelet aggregation
exhibited by each concentration of test compound was accomplished
according to the method of Caprino et al., (Arzneim-Forsch.,
23:1277 [1973]). An ED.sub.50 value was then determined
graphically. Activity of the compounds was scored as follows:
______________________________________ ED.sub.50 (mcg/kg) Activity
Value ______________________________________ No activity 0 >1.0
1 >0.1 .ltoreq. 1.0 2 >0.01 .ltoreq. 0.1 3 >0.001 .ltoreq.
0.01 4 .ltoreq.0.001 5 ______________________________________
B. Evaluation of the Effects of Prostaglandin Analogs III on
Gastric Secretion in the Rat
A procedure based on that described by Lipmann (J. Pharm.
Pharmacol., 21:335 [1968]) was used to assess the influence of test
compounds on gastric secretion. Rats of one sex weighing 150 to 200
g were randomly divided into groups of six animals each and fasted
for 48 hr previous to the experiments, water being available ad
limitum. The animals were anesthetized with ether, the abdomen was
opened through a midline incision and the pylorus was ligated. Test
compounds were diluted from stock solution so as to administer a
dose of 1.5 mg/kg in a volume equivalent to 1 ml/kg. Subcutaneous
injections were applied immediately after surgery and again 2 hr
later, so that a total dose of 3.0 mg/kg was administered.
Dilutions were made with phosphate buffer (pH 7.38) as recommended
by Lee et al. (Prostaglandins 3:29 [1973]), in order to insure
adequate stability of drugs at the subcutaneous depot. Each
compound was tested in one group of rats; an additional control
group received only the vehicle.
Four hr after pyloric ligation the animals were killed with ether,
the cardias ligated and the stomachs removed. The volume of gastric
secretion was measured and the contents centrifuged at 5000 rpm for
10 min. Total acid in the supernatant was titrated against a 0.1 N
sodium hydroxide solution and the amount expressed in mEq.
Volume and total acid values of the treated group were compared
with those of the controls by the "T" test. Anti-secretory activity
was scored according to the following scale:
______________________________________ % decrease in acidity
Activity Value ______________________________________ <26 0
26-50, not significant 1 26-50, significant 2 51-75 3 76-100 4
______________________________________
C. Evaluation of the Effects of Prostaglandin Analogs III on the
Femoral Blood Flow in the Dog
The peripheral vasodilator or constrictor effects of test compounds
were determined in mongrel dogs of either sex, weighing between 10
and 20 kg anesthestized intravenously with 35 mg/kg of sodium
pentobarbital. An external iliac artery was dissected immediately
above the femoral arch for a length of approximately 5 cm and a
previously calibrated, non-connulating electromagnetic flowmeter
sensor with a lumen between 2.5 and 3.5 mm was placed snugly around
the vessel. Cannulas were placed in a branch of the artery arising
distally to the location of the flowmeter sensor for intraarterial
drug administrations, in the contralateral femoral artery for
systemic blood pressure recordings and in the trachea for
artificial respiration with room air. Femoral blood flow and
systemic blood pressure were continuously recorded with an
electromagnetic flowmeter and pressure transducer,
respectively.
After an adequate control period, test compounds were injected
intraarterially at one log-spaced doses ranging from 0.001 to 10
mcg., in a volume of 0.5 ml and at 5 to 10 min intervals. Maximum
changes in bloodflow, as well as any variations in blood pressure,
were tabulated for each dose in absolute values (ml/min and mmHg).
The calculations were made taking as control values those existing
immediately before administration of each dose. The direction of
the observed change (+ for increase and - for decrease) was also
noted. The dose changing bloodflow by 100 ml/min (ED.sub.100
ml/min) was calculated graphically and was used for scoring
activity as follows:
______________________________________ ED.sub.100 ml/min, mcg
Activity Value ______________________________________ >10.0 0
1.0.-10.0 1 0.11-1.0 2 0.01-0.1 3
______________________________________
D. Evaluation of the Effects of Prostaglandin Analogs III on Blood
Pressure and Heart Rate in the Anesthetized Cat
The acute effects of test compounds on blood pressure and heart
rate were determined in cats of either sex anesthetized with a
mixture of pentobarbital sodium (35 mg/kg, i.v.) and barbital
sodium (100 mg/kg, i.v.). Cannulas were placed in the trachea to
allow adequate spontaneous ventilation, in a femoral artery for
blood pressure recording with a strain gage transducer, and in a
saphenous vein for drug administration. Heart rate was recorded by
means of a cardiotachometer driven by the R wave of the
electrocardiogram. After a period of 10 min of stable recordings of
blood pressure and heart rate, the test compound was administered
intravenously at doses increasing from 0.01 to 10.0 mcg/kg, spaced
one log and injected at 10 min intervals. All doses were injected
in a volume of 0.1 ml/kg. Modifications of blood pressure and heart
rate induced by the test compound were expressed both in absolute
units (mmHg and beats/min) and as percent of values recorded
immediately before administration of each dose. Biphasic responses
were tabulated in the order in which they occur. The direction of
the observed changes was also noted (+ for increase and - for
decrease).
Activity of compounds in this test was judged only on the basis of
the degree of hypotension observed. Thus, the ED.sub.50 mmHg (dose
decreasing blood pressure by 50 mmHg) was calculated graphically
and the compound scored according to the following scale:
______________________________________ ED.sub.50 mmHg, mcg/kg
Activity Value ______________________________________ >10.1 0
1.01-10.0 1 0.11-1.0 2 0.01-0.1 3
______________________________________
E. Evaluation of the Effects of Prostaglandin Analogs III on Blood
Pressure in the Hypertensive Rat
The acute antihypertensive activity of test compounds is determined
in rats made hypertensive by the procedure of Grollman (A. Proc.
Soc. Exper. Biol. Med., 57:102, [1944]). Female rats weighing
between 60 and 100 g are anesthetized with ether, the right kidney
approached through a flank retroperitoneal incision, decapsulated
and tied with a figure-of-eight ligature. The animals are left to
recover and two weeks later are again anesthetized and the
contralateral kidney removed. Four weeks after the second operation
the rats are subjected to indirect blood pressure measurements and
those showing systolic pressure values greater than 160 mmHg are
selected for drug testing.
Blood pressure is measured in the tail with an inflatable occluding
cuff placed at the base of the extremity and a pulse detector
located distally. The cuff is inflated to approximately 300 mmHg
and is slowly deflated until pulsations appear, indicating the
level of systolic pressure; diastolic pressure is not recorded by
this procedure. All measurements are carried out in unanesthetized,
unsedated animals maintained in a warm environment during the
recording procedure and for at least 6 hr before. In all cases,
three pressure readings are obtained in succession and mean values
are calculated thereof.
Experiments are carried out in groups of five hypertensive rats in
which systolic pressure is determined immediately before and 2, 4,
6 and 8 hr after the intraperitoneal administration of the test
compound at a dose of 1 mg/kg. Drugs are diluted from stock
solutions with phosphate buffer (Lee et al., Prostaglandins 3:29
[1973]), so as to inject this quantity in a volume of 1 ml/kg.
Changes from control blood pressure values are calculated for each
interval both in mmHg and in per-cent, and evaluated for
significance by means of Wilcoxon's signed rank test (Wilcoxon and
Wilcox, Some rapid approximate statistical procedures, Lederle
Laboratories, Pearl River [1964]). Activity of the compound is
scored as follows:
______________________________________ Blood pressure decrease
Activity Value ______________________________________ Not
significant at any time interval 0 Significant at one time interval
1 Significant at two time intervals 2 Significant at three time
intervals 3 Significant at all four intervals 4
______________________________________
F. Evaluation of the Effects of Prostaglandin Analogs III on the
Rat Uterus
The uterine stimulant effect of test compounds is determined in
segments of uterus obtained from rats (140-160 g) pretreated
subcutaneously with 1 mg/kg of diethylstibesterol 18 hr before the
experiment. The tissues are placed in 10 ml chambers filled with
de-Jalon solution at 29.degree. C. and bubbled with 95% O.sub.2 and
5% CO.sub.2, and prepared for isometric recording with force
displacement transducers. Preparations are stretched to an initial
tension of 1 g and are left undisturbed for 30 min, after which two
responses to 1 mcg/ml of carbachol added to the bath at a 10 min
interval, are obtained (the value of the second response is
recorded). Responses to increasing concentrations of the test
compound (0.001 to 10.0 mcg/ml with one log intervals) are then
recorded every 10 min. Preparations are washed four times after
each response. All doses of drugs are administered in a 0.1 ml
volume. Since it has been observed that the magnitude of the second
response to carbachol, which is approximately 10% greater than the
first, is close to the maximal response of the tissue, such value
is taken as a measure of the sensititity of the particular segment.
Responses to each concentration of the test compound are expressed
in terms of percentage of the second response to carbachol and the
ED.sub.50 (dose producing a response of 50% that of carbachol) is
calculated graphically. Activity is scored according to the
following scale:
______________________________________ ED.sub.50 (mcg/ml) Activity
Value ______________________________________ >10 0 1.001-10 1
0.101-1.0 2 0.01-0.1 3 <0.01 4
______________________________________
G. Evaluation of the Effects of Prostaglandin Analogs III on the
Guinea Pig Trachea
A male guinea pig weighing 200-500 g is killed by a blow on the
head. A 20 mm length of the trachea is dissected (FIG. 1) from the
animal, transferred to a petri dish containing Krebs' solution
aerated with 95% O.sub.2 and 5% CO.sub.2 at 37.degree. C. and cut
longitudinally opposite the tracheal muscle (FIG. 2). The tissue is
then cut transversely three quarters of the distance across, a
second cut in the opposite procedure is continued for the whole
tissue. The ends of the trachea can be pulled to form a zig-zag
shaped strip (FIG. 3). The tracheal strip used in the experiment is
approximately 30 mm when extended under 0.25-0.5 g load in the
tissue bath. Cotton thread is tied to one end of the tissue, and
linen thread to the other. It is attached via the linen thread to a
glass hook in a 5 ml isolated tissue bath containing Krebs'
solution at 37.degree. C. aerated with a mixture of 95% O.sub.2 and
5% CO.sub.2. The opposite end is attached via cotton to an isotonic
Harvard transducer.sup.1. The load on the transducer lever is
small, usually 0.3 g, with a range of 0.25 0.5 g, and the
magnification high, 80 fold using an appropriate twin-channel pen
recorder. A minimum of thirty min is allowed before applying a drug
to the tissue. Drugs are then applied (in volumes of 0.5 ml) at
thirty min intervals, being in contact with the tissue for five min
followed by an overflow washout time of twenty sec.
Prostaglandin E.sub.1, at a bath concentration of 0.1 mcg/ml, is
then tested repeatedly on two such strips, obtained from two
different animals, until two responses (the values of which are
recorded) differing by no more than 25% occur. This concentration
of PGE.sub.1 should elicit a relaxation expressed as from 10 to 30
mm of recorder pan excursion. A test compound is then added to the
same two strips at bath concentrations of 0.01, 0.1, 1.0, and 10.0
mcg/ml and the effects of the compound are recorded. After the test
compound has been evaluated at the highest concentration, PGE.sub.1
is retested at 0.1 mcg/ml (and the value of the response recorded)
to insure that the viability of the strips was retained during the
experiment. The mean of the effects of the test compound on the two
strips is then calculated for each concentration, and, based on the
resulting values, a value judgement is assigned as follows:
______________________________________ Response Value Judgement
______________________________________ More relaxation at 0.01
mcg/ml than that elicited by PGE.sub.1 R4 More relaxation at 0.1
mcg/ml than that elicited by PGE.sub.1 R3 More relaxation at 1.0
mcg/ml than that elicited by PGE.sub.1 R2 More relaxation at 10.0
mcg/ml that that elicited by PGE.sub.1 R1 No effect at any
concentration greater than that elicited by PGE.sub.1 0 More
contraction at 10.0 mcg/ml than the de- gree of relaxation elicited
by PGE.sub.1 C1 More contraction at 1.0 mcg/ml that the de- gree of
relaxation elicited by PGE.sub.1 C2 More contraction at 0.1 mcg/ml
than the de- gree of relaxation elicited by PGE.sub.1 C3 More
contraction at 0.01 mcg/ml than the de- gree of relaxation elicited
by PGE.sub.1 C4 ______________________________________
Table E summarizes the results of the preceeding assays utilizing
preferred examples.
TABLE E ______________________________________ Summary of activity
of Prostaglandin Analogs of Formula III in: Test A: Inhibition of
Human Platelet Aggregation; Test B: Inhibition of a Rodent Gastric
Secretion; Test C: Increase in Canidae Femoral Blood Flow; Test D:
Increase in Normal Feline Blood Pressure and Heart Rate; Test E:
Effects on Blood Pressure in Hypertensive Rat; Test F: Effects on
Rat Uterus; and Test G: Effects on Guinea Pig Trachea.
______________________________________ TR EXAMPLE ACTIVITY VALUE IN
TESTS No. No. A B C D E F G ______________________________________
4569 23B 2 4 0 0 0 0 R3 4570 23A 1 0 0 0 0 2 C2 4645 26B 1 4 1 0 0
0 0 4646 26A 1 0 0 0 0 0 C1 4673 25B 1 3 0 0 1 0 R3 4674 25A 1 2 NT
0 0 0 0 4675 27B 1 2 0 0 NT 0 0 4676 27A 1 0 0 0 0 0 0 4688 24B 1 3
0 0 0 0 R2 4689 24A 1 2 0 0 NT 0 0 4565 28A 1 0 1 0 NT 0 C1 4568
28B 1 0 0 0 0 0 0 4626 29A 1 NT NT NT NT 0 C1 4627 29B 1 0 NT NT NT
0 0 4248 30A 5 4 2 2 1 2 R3 4249 30B 1 0 0 0 0 0 0 4682 31A 1 2 3 1
0 0 0 4681 31B 2 4 2 1 NT 0 R3 4691 32A 1 1 2 0 0 0 R2 4690 32B 4 4
2 1 0 0 R3 4677 33A 1 3 0 0 0 3 R1 4692 33B 1 4 NT 1 0 0 0 4280 34A
1 0 NT NT NT 0 0 4281 35A 1 0 NT NT NT 0 0 4683 35B 1 0 NT NT NT 0
0 4695 36A 1 0 NT NT NT 0 0 4694 36B 1 0 NT NT NT 0 0 4624 37A 1 0
0 0 0 0 0 4625 37B 1 0 0 0 0 0 0 4796 38A 2 2 NT NT NT 0 C3 4797
38B 1 0 NT NT NT 0 NT 4832 39A 1 2 NT NT NT 0 C0 4833 39B 1 0 NT NT
NT 0 C0 4880 40A 1 0 NT NT NT 0 C0 4881 40B 1 0 NT NT NT 0 C4 4882
41A 2 1 NT NT NT 0 C4 4887 41B 1 0 NT NT NT 0 C0
______________________________________ NT: Not tested.
* * * * *